ES2836113T3 - Class of bifunctional compounds with quaternary ammonium salt structure - Google Patents

Abstract

A compound represented by formula I, or a pharmaceutically acceptable salt, solvate, optical isomer thereof: ** (See formula) ** in formula I, having all carbons marked with * the (R) configuration, where: L is (C4-10) aryl or heteroaryl where the heteroaryl heteroatom is selected from N, O and S, and the above groups may be unsubstituted or optionally substituted with one or more substituents selected from halogen, -OR1, -SR1 , -NR1R2, -NHCOR1, -CONR1R2, -CN, -NO2, -COOR1, -CF3 and linear or branched C1-C4 hydrocarbyl; W is independently selected from substituted or unsubstituted (3-7C) cycloalkyl, the substituent is selected from halogen, (1-4C) alkyl, (1-4C) alkoxy, alkoxyhydrocarbyl, and heterocycle; R1 is a divalent group - (R1a) d- (A1) e- (R1b) f-; wherein d, e, and f are each independently selected from 0, 1, 2, or 3, and the number of contiguous atoms in the shortest chain between two nitrogen atoms to which R1 is attached is in the range of 3 to 14; R1a and R1b are each independently selected from (1-10C) alkylene, (2-10C) alkenylene, (1-4C) alkyleneoxy, alkyleneoxyalkyl, alkyleneamido, alkyleneoxy, and alkyleneamino, wherein each from alkylene, alkenylene, alkyleneoxy, alkyleneoxyalkyl , alkyleneamino, alkylenazyloxy, alkyleneamido is unsubstituted or substituted with substituents independently selected from (1-4C) alkyl, chlorine, fluoro, hydroxy, phenyl and substituted phenyl, R1a and R1b may be the same or different; A1 is independently selected from (C3-7) cycloalkylene, (C2-7) alkylene, (C6-10) arylene, (C4-9) heteroarylene, and (C3-8) heterocycloalkylene, where cycloalkylene may be unsubstituted or substituted with 1-4 substituents independently selected from (1-6C) alkyl; each of arylene, heteroarylene and heterocycloalkylene may be unsubstituted or substituted with 1-3 substituents independently selected from halogen, (1-6C) alkyl, (1-6C) alkoxy, -S (1-4C) alkyl, -S (O) -C 1-4 alkyl, -S (O) 2 -C 1-4 alkyl, -C (O) -O (1-4C) alkyl, -NH (1-4C) alkyl, -N = [(1-4C) alkyl] 2, carboxy, nitro, cyano, amido, ester group, trifluoromethyl and trifluoromethoxy; R2 is selected from -N (R2a) C (R2b) (O), -C (R2c) (R2d) OR2e, -N (R2f) - and -O-; R3 is selected from hydrogen, - C (R3a) = C (R3b) -C (O) -, -OC (R3c) (R3d) C (O) -, -N (R3e) CH (R3f) C (O) -, -C (R3g) (R3h) S (O) 2- and -SCO-; provided that when R3 is hydrogen, R2 is selected from -N (R2a) C (R2b) (O) and -C (R2c) (R2d) OR2e; when R3 is selected from -C (R3a) = C (R3b) -C (O) -, -OC (R3c) (R3d) C (O) -, -N (R3e) CH (R3f) C (O) - , -C (R3g) (R3h) S (O) 2- and -SCO-, R2 is selected from -N (R2f) - and -O-; R2a-2f and R3a-3h are each independently selected from hydrogen and (1-4C) alkyl; Y- is selected from pharmaceutically acceptable acid radicals, including inorganic and organic acid radicals; and T represents a hydroxy position on the benzene ring, and is selected from the ortho or meta position of R2 on the benzene ring.

Description

DESCRIPTION

Class of bifunctional compounds with quaternary ammonium salt structure

Technical field

The invention relates to a class of compounds with a bifunctional active quaternary ammonium salt structure of an agonist of p ² adrenoceptors and an antagonist of muscarinic receptors (M receptors). The invention also relates to pharmaceutical compositions including said quaternary ammonium salt compounds, methods of preparing said quaternary ammonium salt compounds, and uses for treating lung disorders.

Previous technique

Asthma and chronic obstructive pulmonary disease (COPD) are the most common diseases in lung disorders, in which COPD is the fourth most deadly disease worldwide and is projected to be the third in 2020. COPD is associated , in general, with smoking tobacco and can also be easily suffered by other environmental pollutions such as harmful occupational dust, gas, steam and industrial mist.

Bronchodilators are the first choice for treating asthma and COPD. Common bronchodilators include a p ² adrenoceptor agonist (eg, albuterol, formoterol, salmeterol, and indacaterol) and an M receptor antagonist (eg, glycopyrronium bromide, ipratropium bromide, tiotropium bromide, etc.). In addition to a single preparation, a compound preparation consisting of a p ² adrenoreceptor agonist and an M receptor agonist is also used for the treatment of lung diseases such as asthma and COPD, and has better therapeutic effect. For example, US patent US6433027 discloses a therapeutic composition that includes the M receptor agonist tiotropium bromide and the p ² adrenoceptor agonist formoterol fumarate.

Furthermore, it was reported that compounds having both p ² adrenoceptor agonist activity and M receptor antagonist activity were to be used for the treatment of asthma and COPD in many bibliographies, such as patent documents WO2004074246, WO2009098448, WO2010004517 , WO2008096127, WO2008149110, WO2008017827, WO2010126025, WO2010015792, WO2005111004, WO2010015792, WO2008041095, WO2005051946, WO2011012896, WO2010123766, etc. The chemical structure of these compounds that have both p ² adrenoceptor agonist activity and M-receptor antagonist activity (abbreviated MABA) consists of three residues, that is, a residue with M receptor antagonist activity, a residue with agonist activity. of p ² adrenoceptors and a connecting moiety. A typical MABA compound has the following structural formula:

Patent document WO2010015792 (Argenta / Astra Zeneca)

Patent document WO2011012896 (Pulmagen / AstraZeneca)

Patent document WO2008041095 (PF4348235, Pfizer)

Said bifunctional compounds are capable of producing bronchodilation effect by two separate modes of action and have unique molecular pharmacokinetics. A phase II clinical study of the representative compound TD5959 has shown that the compound has a good effect on moderate and severe COPD. However, said bifunctional compounds reported in the literature are currently less selective for the M receptor subtype. The drawback of the state of the art is that the vast majority of said bifunctional compounds in the literature are structural compounds of the tertiary amine type, which can pass through the blood-brain barrier, produce other central side effects and have no obvious selectivity for the M ³ receptor subtype, block the M ² receptor to produce many adverse reactions such as high heart rate, high blood pressure, and exacerbation of asthma. Quaternary ammonium salts do not easily cross the blood-brain barrier, and the swallowed part of inhalation preparations is of low bioavailability. Therefore, it is an ideal choice to design and synthesize a MABA compound with a quaternary ammonium salt structure. However, the bibliographies of patent documents WO2004074246 and WO2008017827 reported a plurality of compounds prepared by linking groups to connect the N atoms of two active units of a known active M receptor agonist and a p-adrenoreceptor agonist. ² , but the results of the screened biological activity are not ideal. Patent document WO2004074246 shows that the activity of the M receptor antagonist moiety is significantly reduced by 100 times. Patent document WO2008017827 shows that the activity of the agonist moiety of the p ² adrenoceptors was significantly reduced by more than 100 times, and said MABAs do not achieve the desired results, leading to the abandonment of a similar method to find the quaternary ammonium salt of ideal MABA, no similar study has been reported since.

N. C. Ray et al. (Expert Opinion on Therapeutic Patents, 19 (1), 2009, 1-12) is a patent review of muscarinic antagonist-p-adrenergic antagonist double pharmacology molecules as bronchodilators.

Patent document WO2004106333 describes azabicycloalkane compounds that possess both beta-2-adrenergic receptor agonist and muscarinic receptor antagonist activity.

Patent document WO2014086927 describes compounds that can act as both muscarinic receptor antagonists and beta-2-adrenergic receptor agonists.

Patent document US2012010236 describes quinuclidine compounds having a quaternary ammonium group, which can be used to prevent and treat diseases by blocking the acetylcholine receptor.

Summary of the invention

It is an object of the invention to provide a quaternary ammonium salt compound having p ² adrenoceptor agonist activity and M receptor antagonist activity, and pharmaceutically acceptable salt, solvate, optical isomer and precursor thereof. In view of this, through continuous changes in M receptor agonists and active p ² adrenoceptor agonist units and binding groups, through extensive research and screening, a new class of a compound of Ideal MABA with a quaternary ammonium salt structure. Preliminary experiments in animals have shown that the activity of these compounds achieves the requirement of designing more prominent advantages than the state-of-the-art MABAs: (1) Compared with the state of the art, the intravenous injection dose of the compound of the invention that causes the heart rate to increase is greater than 10 times that of the compound of the state of the art; (2) the compound of the invention has a strong hepatic first-pass effect, but is stable in the lung, and cannot accumulate sufficient toxic dose even if it enters the circulatory system; and (3) the degree of correspondence between the M receptor antagonist activity and the p ² receptor agonist activity of the compound of the invention is very ideal. Compared with the state of the art, the compound of the invention has high selectivity for the M receptor subtype, has characteristics of rapid action, long time of action, less toxic and side effects, and due to the structure of the salt of quaternary ammonium, it is difficult for it to cross the blood-brain barrier, it is easily metabolized, and it is less prone to cardiovascular side effects. The structure of this class of compounds is shown as formula I:

The carbons marked * in formula I are all of the (R) configuration.

L is (C4-10) aryl or heteroaryl, where the heteroaryl heteroatom is selected from N, O and S, and the above groups may be unsubstituted or optionally substituted with one or more substituents selected from halogen, -OR1, - SR1, -NR1R2, -NHCOR1, -CONR1R2, -CN, ^{-NO 2} , -COOR1, -CF ³ and linear or branched ^{C 1} -C ^{4 hydrocarbyl.}

R1, R2 can be a hydrogen atom, straight or branched ^{C 1} -C ^{4 hydrocarbyl.}

L is preferably an unsubstituted phenyl group, pyridyl group, furyl group or thienyl group.

W is independently selected from substituted or unsubstituted (3-7C) cycloalkyl, the substituent is selected from halogen, (1-4C) alkyl, (1-4C) alkoxy, alkoxyhydrocarbyl, and heterocycle. Preferably, W is unsubstituted (3-7C) cycloalkyl, and most preferably W is cyclobutyl, cyclopentyl, and cyclohexyl.

R ¹ is a divalent group - (R ¹ a) d- (A ¹ ) e- (R ¹ b) f-, where d, e, and f are each independently selected from 0, 1,2, or 3, and the number The number of attached atoms in the shortest chain between two nitrogen atoms to which R ¹ is attached is in the range of 3 to 14.

R ^{1 a} and R ¹ b are each independently selected from (1-10C) alkylene, (2-10C) alkenylene, (1-4C) alkyleneoxy, alkyleneoxyalkyl, alkyleneamido, alkylenazyloxy, alkyleneamino, etc., wherein each from alkylene , alkenylene, alkyleneoxy, alkyleneoxyalkyl, alkyleneamino, alkylenazyloxy, alkyleneamido is unsubstituted or substituted with substituents independently selected from (1-4C) alkyl, chloro, fluorine, hydroxy, phenyl and substituted phenyl, R ^{1 a} and R ¹ b may be the same or different.

A ¹ is independently selected from (C3-7) cycloalkylene, (C2-7) alkylene, (C6-10) arylene, (C4-9) heteroarylene, and (C3-8) heterocycloalkylene, etc., where cycloalkylene may be without substituted or substituted with 1-4 substituents independently selected from (1-6C) alkyl. Each of arylene, heteroarylene, and heterocycloalkylene may be unsubstituted or substituted with 1-3 substituents independently selected from halogen, (1-6C) alkyl, (1-6C) alkoxy, -S (1-4C) alkyl, -S (O) -C 1-4 alkyl, -S (O) ² -C 1-4 alkyl, -C (O) -O (1-4C) alkyl, -NH (1-4C) alkyl, -N = [(1-4C) alkyl] 2, carboxy, nitro, cyano, amido, ester group, trifluoromethyl and trifluoromethoxy.

In particular, R ^{1 a} and R ¹ b in the divalent group R ¹ are each independently selected from (1-4C) alkylene, (1-4C) alkyleneoxy, alkyleneamido, etc. A ¹ is independently selected from (C6-10) arylene, etc., wherein the arylene may be unsubstituted or substituted with 1-2 substituents independently selected from halogen, (C1-6) alkyl, (C1-6) alkoxy, carboxy, nitro, cyano, amido or ester group.

Ri is selected in addition to: - (CH2) 3-, - (CH2) 4-, - (CH ² ) s-, - (CH ² ) g-, - (CH ² ) io-, - (CH ² ) ² O (CH ² ) ² -, - (CH2) 2O (CH2) 4-, - (CH2) 3O (CH2) 4-, - (CH2) 4O (CH2) 4-, - (CH2) sO (CH2) 4 -, - (CH2) 2O (CH2) 2O (CH2) 2-, - (CH2) 2O (CH2) 3O (CH2) 2-, -CH2O (CH2) 5OCH2-, - (CH ² ) ² O (CH ² ) ² O (CH ² ) ² O (CH ² ) ² -, - (CH2) 2O (phen-1,4-ylene) (CH2) 2-, - (CH2) 3O (phen-1,4-ylene) CH2-, - (CH2) 3O (3,5-dichloro-phen-1,4-ylene) CH2-, - (CH2) 2CONH (2-methoxy-5-chloro-phen-1,4-ylene) CH2- , - (CH2) 2CONH (3-methyl-phen-1,4-ylene) CH2-, - (CH2) 2CONH (2-methoxy-phen-1,4-ylene) CH2-, - (CH2) 2CONH (phen -1,4-ylene) CH2-, - (CH2) 3CONH (phen-1,4-ylene) CH (CH3) -, - (CH2) 3OCH2 (3-methoxy-phen-1,4-ylene) CH ( CH3) -, - (CH2) 3O (phen-1,4-ylene) C (CH3) 2-, - (CH2) 3O (phen-1,4-ylene) CH (CH2CH3) -, - (CH2) 3O (phen-1,4-ylene) (CH2) 2-, - (CH2) 3O (phen-1,4-ylene) (CH2) 3-, - (CH2) 3O (phen-1,4-ylene) CH2CH (CH3) -, - (CH2) 2OCH2 (phen-1,4-ylene) CH2O (CH2) 2-, - (CH2) 2OCH2 (phen-1,4-ylene) CH (CH3) -, - (CH2) 2O (phen-1,4-ylene) O (CH2) 2-, - (CH2) 3O (2-methoxy-phen-1,4-ylene) O (CH2) 3-, - (CH2) 3O (phen- 1,4-ylene) O (CH2) 3-, - (CH2) 3O (phen-1,4-ylene) CH2C (CH3) 2-, - (CH2) 2O (phen-1,4-ylene) CH2C (CH3) 2-, - (CH2) 2O (phen-1,4-ylene) CH2CH (CH3) -, - (CH2) 2O ( phen-1,4-ylene) (CH2) 2- and - (CH2) 2O (CH2) 3O (CH2) 2-.

R ² is selected from -N (R ² a) C (R ² b) (O), -C (R ² c) (R ² d) OR ² e, -N (R ² f) -, -O- , etc. R ³ is selected from hydrogen, -C (R3a) = C (R3b) -C (O) -, -OC (R3c) (R3d) C (O) -, -N (R3e) CH (R3f) C (O ) -, -C (R3g) (R3h) S (O) 2-, -SCO-, etc., provided that when R ³ is hydrogen, R ² is selected from -N (R ² a) C ( R ² b) (O) and -C (R ² c) (R ² d) OR ² e, and when R ³ is selected from -C (R3a) = C (R3b) -C (O) -, -OC (R3c) (R3d) C (O) -, -N (R3e) CH (R3f) C (O) -, -C (R3g) (R3h) S (O) 2- and -SCO-, R ² is selected of -N (R ² f) - and -O-.

R ^{2 a- 2} f and R ^{3 a- 3} h are each independently selected from hydrogen or (1-4C) alkyl.

R ² is preferably selected from -NHCHO, -CH ² OH, -NH- and -O-.

R ³ is preferably selected from: hydrogen, -CH = CH-C (O) -, -OCH ² C (O) -, -NHCH ² C (O) -, -CH ² S (O) ² - and -SCO -.

T represents a hydroxy position on the benzene ring, and is selected from the ortho or meta position of R ² on the benzene ring.

Y- is selected from pharmaceutically acceptable acid radicals, including inorganic acid radicals such as Br-, Cl-, I-, bicarbonate, carbonate, bisulfate, sulfate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate, and phosphite; and organic acid radicals such as formate, acetate, propionate, isobutyrate, methanesulfonate, ptoluenesulfonate, benzoate, oxalate, tartrate, fumarate, malonate, succinate, suberate, mandelate, phthalate, benzenesulfonate, citrate, glucuronate, galactonate, and amino acid radical. Preferably Y- is Br- or Cl-.

The invention also includes compounds represented by the following structural formulas la-Id:

In the la-Id formulas: the carbons marked with * are the (R) configuration, and L, W, Ri, Y agree with the groups defined above.

The quaternary ammonium salt compounds of the invention have M receptor antagonism and p ² adrenoreceptor agonism. Starting materials are readily available on the market, are prepared by the general methods described below, and can also be prepared by applying other information readily available to those skilled in the art. Specific embodiments and related methods are described herein, and the corresponding compounds can not only be prepared by those skilled in the art using the methods of the invention, but are also prepared using other reagents, methods, and starting materials. . Unless stated otherwise, in addition to the general or preferred method conditions (i.e., reaction temperature, pressure, time, solvent used, molar ratio of reactants, etc.) given in the invention, may be employed other methods and conditions. Although optimal reaction conditions vary with particular reactants or solvents, those of skill in the art can easily determine these reaction conditions by standard optimization procedures.

Furthermore, it will be apparent to those skilled in the art that conventional protecting groups are necessary to prevent unwanted chemical reactions of specific functional groups from interfering with the achievement of the target reaction. Suitable protecting groups for specific functional groups, as well as suitable conditions for the protection and deprotection of such functional groups, are well known in the art. If necessary, protecting groups other than these can also be used herein. The conditions for the protection and deprotection of the protecting groups of various functional groups are described in detail in various literature.

The invention relates to a method of preparing a compound of formula I, and a pharmaceutically acceptable salt, solvate thereof, or mixtures thereof, and of the use of novel intermediates in the preparation of these compounds. The method of preparing a compound of formula I, or a pharmaceutically acceptable salt, solvate, or optical isomer thereof, includes:

(a) reacting intermediate 1 or salt thereof with X ¹ -R ¹ -X ² to generate intermediate 2;

(b) reacting intermediate 2 with intermediate 3 to generate intermediate 4 with protecting groups;

(c) deprotecting groups of intermediate 4 or another compound of formula I with protecting groups to obtain the compound of formula I; Y

(d) exchanging the compound of formula I with a basic anion exchange resin to produce a hydroxide of formula I, and then reacting with various acids to prepare quaternary ammonium salts with various acid radicals; or exchanging the compound of formula I with a specific anion exchange resin to prepare a quaternary ammonium salt with a specific acid radical; or do reacting a halide of the formula I with silver oxide to generate a hydroxide of the formula I and then reacting with other acids to generate quaternary ammonium salts with various acid radicals; or reacting a halide of formula I with a silver salt to produce a quaternary ammonium salt with a corresponding acid radical.

In intermediates 1, 2, 3, 4, the carbons marked with * are designated as R-configurations, hereinafter the same as defined above.

T represents a position of the group on the phenyl ring, and is selected from the ortho and meta position of R ² on the benzene ring.

Q ¹ is hydrogen or a hydroxy protecting group selected from silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc., esters (acyl groups) such as formyl, acetyl, etc., and arylmethyl groups such as benzyl, p-methoxybenzyl, 9-fluorenylmethyl, benzhydryl, etc. Q ² is hydrogen or an amino protecting group selected from benzyl (Bn), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, acetyl, etc. X ¹ and X ² in compound X ¹ -R ¹ -X ² are independently selected from NHQ ² , halogen such as chlorine, bromine, and iodine, and sulfonates such as methanesulfonate, p-toluenesulfonate, and carbonyl. Z is selected from NHQ ² , halogen such as chlorine, bromine and iodine, and sulfonates such as methanesulfonate and p-toluenesulfonate, provided that when X ² is halogen or sulfonate, Z is -NHQ ² , when X ² is - NHQ ² , Z is halogen or sulfonate, and when X ² is carbonyl, Z is -NQ ² and Q ² is hydrogen. R is (1-6C) alkyl, phenyl or substituted phenyl, preferably methyl, ethyl, p-tolyl or phenyl. R ¹ , R ² , R ³ , Y are the same as defined above.

In the above method, when one of the starting materials is a salt, the salt is normally neutralized before or during the reaction, and said neutralization is normally carried out with a base whose molar equivalent is equal to that of the salt.

When Q ¹ and Q ² are protecting groups, they can be removed by methods well known to those of skill in the art.

The reaction between compound 1 and X ¹ -R ¹ -X ² in step (a) is a substitution reaction in which a nucleophilic nitrogen atom in compound 1 replaces X ¹ in X ¹ -R ¹ -X ² to form a quaternary ammonium salt.

Step (a) is normally carried out in a protic solvent, a zwitterionic solvent, or an inert solvent such as methanol, ethanol, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and the like. The reaction is normally carried out in the range of 10-100 ° C until the reaction is substantially complete. The separation of the product is carried out by a usual purification method, that is, extraction, recrystallization, column chromatography and the like.

The preparation of intermediate 1 was carried out by the method reported in the literature (patent document WO2015007073A1), that is, it was prepared by intermediate 5 and intermediate 6 in the presence of a strong base.

^ < W 1

5

The molar ratio between the two intermediates is intermediate 5: intermediate 6 = 1: 1-2, preferably 1: 1.2. The reaction is carried out in a zwitterionic solvent, an aprotic solvent, or an inert solvent, and the usual solvent is usually acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and the like. The reaction temperature is in the range of 10-100 ° C, preferably 70-100 ° C. The strong base is selected from sodium hydride, sodium amide, and the like. The molar ratio of the strong base to intermediate 6 is 1-2: 1, preferably 1.2: 1. The reaction time is 2-10 hours, preferably 5-8 hours.

Intermediate 6 may be commercially available.

Intermediate 5 can be prepared by Intermediate 7:

In intermediate 7, Q ³ is selected from methyl, phenyl, p-tolyl, and the like. Intermediate 7 removes a sulfonic acid molecule in the molecule under alkaline condition to generate the intermediate product of epoxy compound 5, and the reaction solvent is selected from methanol, ethanol, acetone, N, N-dimethylformamide, N, N -dimethylacetamide, dimethyl sulfoxide and the like. The base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like. The reaction time is 2-10 hours, preferably 3-6 hours. The reaction temperature is 10-100 ° C, preferably 20-50 ° C.

The preparation of intermediate 7 is derived from intermediate 8:

Intermediate 8 is reacted with sulfonyl chloride under alkaline condition to generate intermediate 7. The solvent used in the reaction is an inert solvent such as dichloromethane, chloroform, acetonitrile, acetone, N, N-dimethylformamide, N, N -dimethylacetamide, dimethyl sulfoxide and the like. The base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine, triethylamine, N-methylmorpholine, and the like. The reaction time is 2-10 hours, preferably 3-6 hours. The reaction temperature is 10-100 ° C, preferably 20-50 ° C.

Intermediate 8 is prepared by Intermediate 9 in the R configuration:

Intermediate 9 is reduced with a reducing agent such as sodium borohydride in the presence of a Lewis acid to obtain intermediate 8 directly. The reaction solvent is an inert solvent such as dichloromethane, chloroform, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, or a mixture thereof. Lewis acid is aluminum trichloride, tin tetrachloride, titanium tetrachloride, or the like. The reaction time is 2-10 hours, preferably 3-6 hours. The reaction temperature is 10-100 ° C, preferably 20 50 2C.

Intermediate 9 is obtained by chiral resolution of its racemate, the resolution method used can be with reference to patent WO9942460, and patent document CN100408549C.

The methods of preparation of the various types of compounds represented by the formula X ¹ -R ¹ -X ² are described in detail in the preparation and examples.

In step (b), intermediate 2 and intermediate 3 are subjected to nucleophilic substitution reaction to generate intermediate 4, that is, an amino nitrogen atom replaced the leaving group. The reaction is usually carried out in a protic solvent, a zwitterionic solvent, or an inert solvent such as methanol, ethanol, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and the like. The reaction is usually carried out at a temperature in the range of 10-100 ° C, preferably 60-100 ° C, until the reaction is substantially complete.

When X ² in intermediate 2 is -OSO ² R, R is as defined above, and the structural formula of intermediate 2 is formula 10:

The preparation of formula 10 is prepared by reacting formula 11 with a sulfonyl chloride under alkaline condition. The reaction solvent is dichloromethane, tetrahydrofuran, ethyl ether, isopropyl ether, acetonitrile, acetone, or a mixture thereof. The reaction temperature is room temperature. The base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, N-methylmorpholine, diisopropylamine, and the like. The sulfonyl chloride is selected from methanesulfonyl chloride and p-toluenesulfonyl chloride. The molar ratio of formula 11 to sulfonyl chloride is 1: 1-2, preferably 1: 1.05. The molar ratio of intermediate 2 to base is 1: 1-2, preferably 1: 1.2.

In intermediate 3, Z is -NHQ ² , Qi and Q ² are as defined above, the structural formula of intermediate 3 is formula 12:

In intermediate 3, when Z is a leaving group such as Br-, and Q ¹ is as defined above, the structural formula of intermediate 3 is formula 13:

In Formula 12, when R ³ is hydrogen, R ² is -CH ² OQ ⁴ and T is in the ortho position. Q ¹ and Q ² are respectively as described above. Q ⁴ is hydrogen or a hydroxy protecting group selected from silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like, esters (acyl groups) such as formyl, acetyl and the like, and arylmethyl groups such as benzyl, p-methoxybenzyl, 9-fluorenylmethyl, benzhydryl, and the like. The structural formula of the compound of formula 12 is formula 14:

The preparation of formula 14 is carried out by reacting formula 15 with Q ² NH ² in alkaline condition under pressure or by heating. The reaction solvent is alcohol, water, or Q ² NH ² . The reaction temperature is 50-120 ° C, preferably 80-110 ° C. The reaction time is 1-10 hours, preferably 4-6 hours.

In formula 15, Q ⁴ is as described above. Formula 15 is the product of the R configuration obtained by the chiral reduction of formula 16 using borane-dimethyl sulfide solution or tetrahydrofuran in the presence of a chiral catalyst. The reaction solvent is selected from tetrahydrofuran, dioxane, ethyl ether, dichloromethane, and the like. Reaction time is ^1-6 hours. The reaction temperature is -5-50 ° C, preferably 0 to 40 ° C.

In formula 16, Q ¹ and Q ⁴ are the same as defined above, and the method of preparing them is carried out by reacting formula 17 with bromine in solution. The reaction solvent is selected from tetrahydrofuran, dioxane, ethyl ether, isopropyl ether, dichloromethane, chloroform, and a mixture thereof. The reaction time is 1-6 hours. The reaction temperature is -5-50 ° C, preferably -5-30 ° C.

In formula 17, Q ¹ and Q ⁴ are the same as defined above, and the preparation method thereof is carried out by reacting 4-hydroxy-3-hydroxymethylacetophenone with a compound containing hydroxy protecting group under condition alkaline, for example with benzyl bromide.

In formula 12, when R ³ is hydrogen, R ² is -NHCHO, and T is in the ortho position, Q ¹ and Q ² are respectively as described above, and the structural formula thereof is formula 18:

Formula 18 is prepared by reacting Formula 19 with Q ² NH ² under pressure or by heating. The reaction solvent is selected from alcohols, water, tetrahydrofuran, dioxane, or Q ² NH ² . The reaction temperature is 50-120 ° C, preferably 80-110 ° C. The reaction time is 1-10 hours.

In formula 19, Q ¹ is the same as defined above, and its preparation is carried out by chiral reduction of formula 20 using borane-dimethyl sulfide or tetrahydrofuran solution in the presence of a chiral catalyst giving the R configuration. The reaction conditions are the same as for the preparation of compound 15.

In formula 20, Qi is the same as defined above, a compound of formula 20 is prepared from a compound of formula 21 and anhydrous formic acid. The condensing agent of the reaction is selected from 1,3-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) and the like. A compound of the formula 20 can also be prepared by reacting a mixed anhydride prepared by acetic anhydride and formic acid with the formula 21. The reaction solvent is selected from dichloromethane, tetrahydrofuran, anhydrous formic acid, or a mixture thereof. Reaction time is 2-8 hours. The reaction temperature is 5-50 ° C, preferably the temperature is 5-30 ° C.

In the compound of the formula 21, Q ¹ is the same as defined above, and the compound of the formula 21 is prepared by reducing the compound of the formula 22 with a metal and ammonium chloride. The reaction solvent is selected from water, alcohols such as methanol, ethanol, and the like. The metal is selected from reducing iron powder, zinc powder, and the like.

In Formula 22, Q ¹ is the same as defined above, and Formula 22 is prepared by reacting Formula 23 with bromine in solution. The reaction solvent is tetrahydrofuran, dioxane, ethyl ether, isopropyl ether, dichloromethane, chloroform, or the like. The reaction time is 1-6 hours. The reaction temperature is -5-50 ° C, preferably the temperature is 5-30 ° C.

In formula 23, Q ¹ is the same as defined above, and formula 23 is prepared by reacting 4-hydroxy-3-nitroacetophenone with a compound containing hydroxy protecting group under alkaline condition, for example by reacting with benzyl bromide.

In formula 12, Q ¹ and Q ² are the same as defined above. When R ² is -NH-, R ³ is -CH = CH-CO-, and T is in the ortho position, the compound represented by formula 12 is formula 24:

The preparation method of the formula 24 is carried out by a nucleophilic addition reaction of the formula 25 and Q ² NH ² , and the reaction solvent is selected from methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, isopropyl ether and a mixture thereof, preferably methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane. The reaction temperature is 10-100 ° C. Reaction time is 2-8 hours. Qi and Q ² are respectively as described above.

In formula 25, Qi is the same as defined above, and a compound of formula 25 is cyclized from a compound of formula 26 under alkaline condition. The base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and the like. The reaction solvent is water, methanol, ethanol, acetonitrile, acetone, butanone or the like, preferably methanol, ethanol, acetone or water. The reaction temperature is 10-100 ° C, preferably the temperature is 10-30 ° C. The reaction time is 1-5 hours.

In the structural formula of formula 26, Q ¹ is the same as defined above. Its preparation is carried out by selective reduction of formula 27 with borane in the presence of a chiral catalyst to form an alcohol in the R configuration. The catalyst used in the reaction is (1 R, 2S) - (+) - indanol. The reaction solvent is selected from N, N-dimethylformamide, N, N-diethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, tetrahydrofuran, ethyl ether or isopropyl ether and the like, preferably tetrahydrofuran or ethyl ether. The molar ratio between formula 27 and (1R, 2S) - (+) - indanol is 1: 0.01 -0.2. The molar ratio between formula 27 and borane is 1: 1.1-2.5. The reaction temperature is 0-50 ° C, preferably the temperature is 0-30 ° C. Reaction time is 4-10 hours.

In formula 27, Qi is the same as defined above. The preparation method thereof is carried out by reacting formula 28 with bromine in a solution. The reaction solvent is selected from tetrahydrofuran, dioxane, ethyl ether, isopropyl ether, dichloromethane, chloroform, and the like. The reaction time is 1-6 hours. The reaction temperature is -5-50 ° C, preferably the temperature is 0 to 30 ° C.

The preparation of formula 28 takes 5-acetyl-8-hydroxyquinoline as starting material which is reacted with QiX under alkaline condition to generate formula 28. X is a leaving group, selected from halogen such as chlorine, bromine and iodine, sulfonate such as methanesulfonate and p-toluenesulfonate. The base is selected from potassium carbonate, sodium carbonate, and the like. The reaction solvent is selected from methanol, ethanol, acetone, butanone, tetrahydrofuran, dioxane, dichloromethane, chloroform, ethyl ether, isopropyl ether, acetonitrile and the like, preferably acetone, tetrahydrofuran or acetonitrile.

In formula 12, Qi and Q ² are the same as defined above. When R ² is -NH-, R ³ is -O-CH ² -CO-, and T is in a meta position, the compound represented by formula 12 is formula 29:

The preparation method is carried out by a nucleophilic addition reaction of the formula 30 and Q ² NH ² , and the reaction conditions are similar to those of the formula 24. Q ¹ and Q ² are respectively as described above .

Formula 30 is prepared from Formula 31, and its preparation method is similar to Formula 25, where Qi is the same as defined above.

Formula 31 is prepared from Formula 32, and its preparation method is similar to that of Formula 26, where Q ¹ is the same as defined above.

Formula 32 is prepared from formula 33, and its preparation method refers to the preparation method of formula 27, where Q ¹ is the same as defined above.

Formula 33 is prepared by reacting Formula 34 with chloroacetyl chloride under alkaline condition. The preparation conditions are that: the molar ratio between formula 34 and chloroacetyl chloride is 1: 1-2, preferably 1: 1.05. The base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate or low concentration sodium hydroxide solution and the like, and the molar ratio between formula 34 and the base is 1: 1-3, preferably 1: 1 ,5. The reaction temperature is 10-100 ° C, preferably 20-60 2C.

Formula 34 is derived from Formula 35 in which a nitro group is reduced to give an amino group. The preparation method can adopt a hydrogenation method, and platinum oxide is used as a catalyst for selective hydrogenation. The reaction solvent is selected from methanol, ethanol, tetrahydrofuran, and a mixture thereof. The temperature is 10-50 ° C, preferably 20-30 ° C. The pressure is 0.5-4 MPa. Optionally, reducing iron powder is used for selective reduction in aqueous ammonium chloride solution so that a nitro group is reduced to an amino group. The solvent is selected from methanol, ethanol, tetrahydrofuran, and a mixture thereof. The molar ratio of formula 34 to ammonium chloride is 1: 1-4, preferably 1: 2. The molar ratio between the formula 35 and the reducing iron powder is 1: 1-5, preferably 1: 2.

Formula 35 is prepared by nitration of formula 36. The reaction solvent is glacial acetic acid, and the reaction temperature is -5-50 ° C, preferably 0-30 ° C.

Formula 36 is prepared by reacting 2,4-dihydroxyacetophenone with Q ¹ X in weak alkaline condition, and Q ¹ X is the same as defined above. The base is selected from sodium bicarbonate, potassium bicarbonate, a mixture thereof, and the like. The molar ratio of 2,4-dihydroxyacetophenone to the base is 1: 1. The molar ratio of 2,4-dihydroxyacetophenone to Q ¹ X is 1: 1. The reaction temperature is 10-50 ° C, and the reaction time is 2-5 hours.

In step (c), intermediate 4 or another target compound is reduced with a protecting group to generate the target compound. Any suitable reducing agent can be used in the reaction, for example in catalytic hydrogenation. The catalyst is selected from Pd / C, Raney nickel, platinum oxide, and a mixture thereof, and a metal hydride reagent such as sodium triacetylborohydride and the like. The reaction solvent is selected from methanol, ethanol, and a mixture thereof.

In step (d), the compound of formula I is exchanged with a basic anion exchange resin to produce a hydroxide of formula I, such as OH- resin, and is then reacted with various acids to prepare salts of quaternary ammonium with various acid radicals, including various acid radical salts as mentioned above. Optionally, the compound of formula I is exchanged with a specific anion exchange resin to produce a quaternary ammonium salt with a specific acid radical. Optionally, a halide of formula I is reacted with silver oxide to generate a hydroxide of formula I and then reacted with other acids to generate quaternary ammonium salts with various acid radicals. Optionally, a halide of formula I is reacted with a silver salt such as silver sulfate or silver nitrate to produce a quaternary ammonium salt with a corresponding acid radical.

In specific embodiments, certain specific compounds of formula I are prepared by method (a1) - (d1). The method includes compounds having the following structural formula or optional pharmaceutically acceptable salts or solvates thereof or optical isomers thereof, and mixtures thereof.

On the other hand, the invention relates to a pharmaceutical composition of a compound of formula I, which includes an acceptable pharmaceutical carrier, and the pharmaceutical composition can selectively contain other therapeutic components, such as steroidal anti-inflammatory drug, phosphodiesterase inhibitor (PDE -4) and their pharmaceutically acceptable salts, solvates and therapeutically effective amount of optical isomers.

The compound of the formula I of the invention is used, in general, in the form of compositions or preparations for patients. These compositions can be applied to patients by any acceptable route of administration, including, but not limited to, inhalation, oral, nasal, topical (including transdermal), and parenteral administration. That is, any form of the compound of the invention suitable for any particular mode of administration (including free base, pharmaceutically acceptable salts or solvates thereof, etc.) can be used in the pharmaceutical composition of the invention.

The pharmaceutical composition of the invention generally contains a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof. In general, said pharmaceutical composition contains from about 0.001% to about 100% by weight of the active ingredient.

Any conventional vehicle or excipient can be used in the invention, and the selection of a particular vehicle or excipient, or a combination of vehicle and excipient, depends on the mode of administration or medical condition or type of disease to treat a particular patient. The technology of preparing the pharmaceutical composition for a specific mode is within the knowledge of those skilled in the art. In addition, the vehicle or excipient or the combination of the vehicle and the excipient can be purchased commercially.

Representative examples as pharmaceutically acceptable carriers include, but are not limited to: (1) saccharides such as glucose, lactose, sucrose, etc .; (2) starches, such as cornstarch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, cellulose acetate, etc .; (4) talc; (5) excipients, such as cocoa butter and waxes; (6) oils, such as olive oil, soybean oil, etc .; (7) alcohols, such as ethanol, propylene glycol, glycerol, sorbitol, polyethylene glycol, mannitol, etc .; (8) esters, such as ethyl oleate and ethyl laurate; (9) pyrogen-free water; (10) isotonic saline; (11) phosphate buffer solution; (12) compressed propellant gases, such as chlorofluorocarbons, hydrofluorocarbons, etc .; and (13) other miscible non-toxic substances used in pharmaceutical compositions.

The composition of the invention is prepared, in general, by thoroughly mixing the compound of the invention with optionally one or more carriers. If necessary, the homogeneous mixture obtained in the invention can be plasticized or filled into tablets, capsules, pills, cans or cartridges using conventional equipment and methods.

The pharmaceutical composition of the invention is suitable for administration by inhalation. Compositions for administration by inhalation are usually in the form of aerosols or a powder inhalation. Such compositions are generally administered using well known delivery devices, such as a nebulizer, metered dose inhaler (MDI) or dry powder inhaler (DPI) or other similar inhalation devices.

The composition containing the active principle of the invention is atomized and administered by nebulizer. Atomizing devices can normally generate high speed air flow to atomize the pharmaceutical composition containing the active ingredient to be inhaled into the airways by patients. Therefore, the active ingredient is normally dissolved in a suitable solvent to prepare a solution and placed in the nebulizer. Optionally, the active ingredient is micronized and is in combination with a suitable carrier to form a suspension of micronized particles suitable for inhalation. Micronization is generally defined as greater than or equal to 90% of particles with a diameter less than 10 gm. Suitable atomizing devices are commercially available.

Representative pharmaceutical compositions using nebulizer include isotonic aqueous solution or ethanol solution containing 0.05 gg / mL to 10 mg / mL of the compound of formula I or pharmaceutically acceptable salt, or solvate, or optical isomers thereof.

The pharmaceutical composition contained in the invention is administered by inhalation using a dry powder inhaler. Dry powder inhalers are normally administered in such a way that the active ingredient forms a flowable powder in the patient's air flow during inhalation. Therefore, the active principle is normally formulated together with a suitable excipient to obtain a flowable powder, for example lactose as an excipient.

Representative pharmaceutical compositions for dry powder inhalers include dry lactose having a particle size between about 1 gm and 100 gm and the aforementioned micronized particles of a compound of formula I, or a pharmaceutically acceptable salt or solvate or optical isomer. of the same.

The dry powder formulation can be prepared by dry mixing the active ingredient with the excipient, or without the excipient, and then the pharmaceutical composition is filled into a dry powder dispenser or an inhalation cartridge or capsule for use with a dry powder delivery device.

Dry powder delivery devices are commercially available.

The pharmaceutical composition containing the active ingredient of the present invention is administered by inhalation using a metered dose inhaler. Said metered dose inhalation device uses compressed propellant gas to discharge a metered amount of the active ingredients or pharmaceutically acceptable salts thereof. Thus, the pharmaceutical composition administered by the metered dose inhaler is contained in a solution or suspension propelled by liquefaction.

Representative pharmaceutical compositions for metered dose inhalers include 0.001% to about 3% by weight of a compound of formula I or a pharmaceutically acceptable salt or solvate or optical isomer thereof, about 0% to about 40% of the cosolvent, ethanol or diols. , preferably 5% to about 30%, and about 0% to 3% by weight of a surfactant. The remainder is hydrofluoroalkane propellant (HFA).

Such a composition is normally prepared by adding chilled or pressurized hydrofluoroalkanes to a suitable container containing the active ingredient, ethanol (if present) and surfactant (if present). To prepare the suspension, the active ingredient is micronized and then mixed with the propellant. The preparation is then placed in an aerosol can to form a part of a metered dose inhaler. The suspension preparation can also be prepared by a spray drying method to form a surfactant coating on the surface of the active ingredient microparticles.

Methods and preparations for preparing inhalable particles and other examples suitable for administration by inhalation are discussed in the literature.

The composition of the invention is suitable for oral administration. The pharmaceutical composition for oral administration can be capsule, tablet, pill, powder, granule, flat capsule and sugar-coated pill, or it can be prepared in aqueous or non-aqueous solution or suspension, or prepared in water-in-oil emulsion or oil in water, or prepare in syrup. They all contain a predetermined amount of the active principle of the compound of the invention.

When the solid dosage form is administered, the composition of the invention includes the compound of the invention as active ingredient and one or more pharmaceutically acceptable drug carriers as appropriate, for example, (1) fillers or fillers, such as starch, sucrose, silicic acid, etc .; (2) adhesives, such as carboxymethylcellulose, polyvinylpyrrolidone, etc .; (3) humectants, such as glycerol; (4) disintegrants, such as calcium carbonate, starch, etc .; (5) lubricants, such as magnesium stearate, talc, solid polyethylene glycol, or mixtures thereof; and (6) absorbent, such as kaolin, etc.

Release agents, humectants, coating agents, sweeteners, antioxidants, perfume agents, flavorings and preservatives may also be present in the composition of the invention. Pharmaceutically acceptable antioxidants include, but are not limited to, the following substances: water soluble antioxidants, such as sodium sulfite, ascorbic acid, cysteine hydrochloride, etc .; fat soluble antioxidants, such as propyl gallate, alpha-tocopherol, etc .; and metal chelating agent, such as citric acid, sorbitol and ethylenediaminetetraacetic acid (EDTA), etc.

Coating agents for tablets, capsules, and pills include, but are not limited to, cellulose acetate phthalate (CAP), carboxymethylethylcellulose (CMEC), and the like.

The composition of the invention can also be formulated in a slow release agent to control the slow release of active principles, for example, carboxymethylcellulose or other polymer matrices, liposomes or microspheres are used in different proportions to prepare the slow-controlled agent.

Liquid pharmaceutical forms suitable for oral administration include suspensions, syrups, emulsions, microemulsions and solutions, etc. Liquid pharmaceutical forms contain active ingredients and inert diluents, such as water and other solvents, solubilizers and emulsifiers, etc. Typical representatives are the following: oils (olive oil, etc.), glycerin, polyethylene glycol, sorbitan fatty acid esters, or mixtures thereof.

The pharmaceutical composition of the invention can also be a mixture formed by a compound of formula I or a pharmaceutically acceptable salt, solvate or optical isomer thereof and mixtures thereof with other drugs for therapy by co-administration. For example, the pharmaceutical composition of the invention includes: one or more other bronchodilators such as PDE ³ inhibitor, p ² adrenoreceptor agonist, etc .; anti-inflammatory agents such as steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, PDE ⁴ inhibitors, etc .; M receptor agonists; anti-infective agents such as Gram-negative and Gram-positive antibiotics, antiviral drugs, etc .; antihistamines; protease inhibitor; and afferent blockers such as D ² agonists. Other therapeutic agents can be applied in the form of pharmaceutically acceptable salts or solvates. Furthermore, other therapeutic agents can also be applied in the form of optical isomers.

^{Representative p 2} adrenoreceptor agonist that can be used in combination with the compound of the invention (in addition to the compounds of the present invention) includes, but is not limited to, salmeterol, salbutamol, levalbuterol, formoterol, indacaterol, wielandt, arformoterol, salmefamol, fenoterol, isoetharine, metaproterenol, bitolterol, pirbuterol, etc., or pharmaceutically acceptable salts thereof.

Representative steroidal anti-inflammatory agents (other than the compound of the invention) that can be used in combination with the compound of the invention include, but are not limited to, methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, beclomethasone ester, budesonide, flunisolide , mometasone ester, triamcinolone, rofleponide, ciclesonide, etc., or pharmaceutically acceptable salt thereof. When in use, the steroidal anti-inflammatory agents will be present in the composition in a therapeutically effective amount, typically the amount of steroid is between 0.05 pg and 500 pg.

Other suitable compositions include compositions formed by the compound represented by formula I of the invention and other anti-inflammatory drugs. For example, typical representative drugs of non-steroidal anti-inflammatory drugs are as follows: NSAIDs such as nedocromil sodium, cromolyn sodium, etc., phosphodiesterase (PDE) inhibitors such as theophylline, PDE ⁴ inhibitors, mixed PDE ^{3 inhibitors} / PDE ⁴ , etc., leukotriene antagonists such as montelukast, protease inhibitors, cytokine antagonists, and cytokine synthesis inhibitors.

Representative M receptor agonists that can be used in combination with the compounds of the present invention (in addition to the compounds of the invention) include, but are not limited to, glycopyrrolate, ipratropium bromide, tiotropium bromide, atropine, sulfate Atropine, Atropine Oxide, Methylatropine Nitrate, Homatropine Hydrobromide, Scopolamine Hydrobromide, Oxitropium Bromide, Methantheline Bromide, Propantheline Bromide, Anisotropin Methyl Bromide, Clidinium Bromide, Isopropalenine Iodide, Plenzoeplamide, Bromide , methoctramine, etc., or pharmaceutically acceptable salts thereof.

Antihistamine drugs that can be used in combination with the compounds of the invention include, but are not limited to, ethanolamines such as clemastine fumarate, carbinoxamine maleate, diphenhydramine hydrochloride, dimenhydrinate, etc., ethylenediamines such as pyrilamine maleate, tripelenamine hydrochloride and tripelenamine citrate, etc., alkylamines such as chlorpheniramine, acrivastine, etc., piperazines such as hydroxyzine hydrochloride, acid-resistant hydroxyzine, cyclizine hydrochloride, cyclizine lactate, meclizine hydrochloride, cetirizine hydrochloride, etc., piperidines such as astemizole, levocabastine hydrochloride, loratadine and its analogues, terfenadine, fexofenadine hydrochloride, azelastine hydrochloride, etc., and pharmaceutically acceptable salts thereof.

Effective therapeutic doses of other drugs administered in combination with the compounds of the invention are in the range of about 0.005 mg to about 10 mg each time.

The invention also relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, solvate, optical isomer thereof, or a mixture thereof, to prepare a medicament for treating respiratory diseases, including COPD, asthma, rhinitis and the like.

The compound of the invention has both p ² adrenoceptor agonist and M receptor antagonist activities, making it suitable for treating diseases mediated by p ² adrenoceptors and M receptors. That is, diseases that can be alleviated using p ² adrenoceptor agonists and M receptor agonists. Such disease includes pulmonary disorders or diseases related to reversible airway obstruction, such as COPD, asthma, pulmonary fibrosis, etc.

A method of treating lung diseases is disclosed, which includes administering an effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvate or optical isomer thereof to a patient in need of treatment. In the treatment of diseases, the compound of the invention is normally administered by inhalation in the form of multiple daily doses, single daily doses, or single weekly doses. The dose is about 1.0 pg to about 200 pg each time.

When administered by inhalation, the compound of the invention has bronchiectasis, whereby the invention relates to a method of providing bronchiectasis to a patient, which includes administering an effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvate or optical isomer thereof to the patient in need of treatment. Dosage is about 1.0 pg to about 200 pg each time.

Also described is a method of treating chronic obstructive pulmonary disease or asthma, which includes administering an effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvate or optical isomer thereof to a patient in need of treatment. In the treatment of COPD or asthma, it is administered in a multiple dose and single daily dose mode, with the dose varying from about 1.0 pg to about 200 pg each time.

When the compound of the invention is used in the treatment of lung diseases, the compound of the present invention can optionally be administered in combination with other therapeutic agents. Especially when the compound of the invention is combined with steroidal anti-inflammatory drugs, the two active ingredient compositions of the invention can provide triple therapy, namely p ² adrenoreceptor agonist effect, M receptor antagonist effect and anti-inflammatory effect. The composition containing two active ingredients of the invention is, in general, easier to prepare compared to the composition containing three active ingredients. Therefore, the two-component composition is superior to the three-component composition. The pharmaceutical composition of the invention may contain a therapeutically effective amount of a steroidal anti-inflammatory agent.

The compound of the invention shows agonist activity of p ² adrenoceptors and antagonist activity of M receptors. Among other properties, the compounds that are of special interest are the compounds with Ki value of the inhibition constant of the M ³ receptor subtype and CE ⁵⁰ agonist activity of p ² adrenoceptors less than 100 nm, especially compounds with both values less than 10 nm. In addition, in in vitro experiments or similar experiments, attention should be paid to compounds with similar Ki value of the inhibition constant. of the M ³ receptor subtype and EC ⁵⁰ value of the p ² adrenoceptor agonist activity. For example, attention can be paid to compounds for which a ratio between the Ki value of the inhibition constant of the M ³ receptor subtype and the EC ⁵⁰ value of the p ² adrenoceptor agonist activity is approximately 1:30 a about 30: 1, particularly 1:20 to 20: 1, more particularly about 1:10 to about 10: 1, and most particularly 1: 5 to about 5: 1.

A method of treating COPD is disclosed, which includes administering an effective dose of a compound having M ³ receptor antagonist activity and p ² adrenoceptor agonist activity to a patient in need of treatment.

In certain specific examples, the compound of the invention may have weak M receptor antagonist activity or p ² -adrenoceptor agonist receptor binding activity, but can still be used alone as M receptor antagonist or p 2 -adrenoceptor receptor antagonist activity. p ² adrenoceptors.

When describing the compound, composition, method and process of the invention, unless otherwise indicated, the following terms have the following meanings.

The term "alkyl" refers to unsubstituted linear or branched saturated hydrocarbons. Unless defined otherwise, such alkyl groups generally contain 1 to 10 carbon atoms. Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like.

The term "alkoxy" refers to a monovalent group of the formula (alkyl) -O-, where alkyl is as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

The term "arylene" refers to a divalent group on an aromatic ring, including substituted and unsubstituted aromatic rings. Representative arylene groups include 1,4-phenylene, 2-methoxy-1,4-phenylene, 2,5-furylidene, and the like.

The term "heterocyclylene" refers to a divalent group of heteroaromatic cyclic hydrocarbons, including substituted and unsubstituted heterocycloalkanes. Representative examples include 2,3-tetrahydrofurylidene, 2,4-tetrahydropyrrolylene, and the like.

The term "alkylene amide group" refers to a divalent group containing both alkyl and amide groups, including substituted and unsubstituted alkylene amide groups. Representative alkylene groups include 2-oxopropylamin-1,4-ylidene, 2-oxoethylamin-1,3-ylidene, and the like.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

The term "pharmaceutically acceptable salt" refers to a salt that can be used to administer to a patient. This salt can be obtained from pharmaceutically acceptable inorganic and organic bases, and can also be obtained from pharmaceutically acceptable inorganic and organic acids, including salts of active compounds prepared with relatively non-toxic acids or bases according to the specific substituents present in the compound described in This document. Examples of pharmaceutically acceptable salts derived from inorganic bases include, but are not limited to, ammonium, calcium, potassium, sodium, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines including substituted amines, cyclic amines, natural amines, and the like, such as, but not limited to, betaine, caffeine, choline, and the like. When the compound of the invention contains relatively basic functional groups, salts can be obtained by contacting said compound in free form with a sufficient amount of the desired acid alone or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as, but not limited to, nitrates, carbonates, bicarbonates, phosphates, sulfates, bisulfates, hydrochlorides, hydrobromates, and the like; and salts derived from relatively non-toxic organic acids such as, but not limited to, acetic acid, succinic acid, fumaric acid, mandelic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.

The forms of the compound involved in the invention and salt thereof can be converted to each other by methods conventional in the art. For example, ammonium salts can be separated into free forms by contacting the salts with bases or acids in a conventional way. The compound in free form is added to the acid or base to obtain other salt forms. Some physical properties of the free form of the compound, such as solubility in polar solvents, are different from the various salt forms, but for the purposes of the invention, the salt has the same therapeutic effect as the parent form of the compound.

In addition to the salt form, compounds in the form of prodrug esters are also described. The "prodrugs" of the compounds described herein are those compounds that are susceptible to chemical changes in a physiological environment to obtain the compounds of the present invention.

"Precursor group" refers to a type of protecting group that can transform a drug into a prodrug when the functional group used to mask the active drug is formed into a "precursor moiety". The groups Precursors are normally attached to drug functional groups by linkages that can be cleaved under specific conditions of use. Thus, the parent group is a part of a parent moiety that is cleaved under specific conditions of use to release the functional groups.

Specific examples of suitable precursor groups and their corresponding precursor moieties will be apparent to those skilled in the art.

Certain compounds of the invention have an asymmetric carbon atom (optical center of rotation) or double bond. Its racemate, diastereomer, geometric isomer, and optical isomer are all within the scope of the invention. These isomers can be resolved or synthesized asymmetrically by conventional methods to produce the "optically pure" isomers, that is, substantially free of their other isomers. For example, if a specific enantiomer of the compound of the invention is required, it can be prepared by asymmetric synthesis or by derivatization with chiral auxiliary reagent, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to obtain the pure desired enantiomer. . Optionally, the different diastereoisomers formed according to their multiple chiral centers are separated by a preparation column, for example, compounds 61,70, 82, 98 and other compounds have a chiral carbon in their R1 structures, that is, the separation is carried out out by this method. Alternatively, when the molecule contains a basic functional group, such as an amino group or an acid functional group such as a carboxyl group, a salt of the asymmetric isomer is formed with an appropriate rotating active acid or base, and then the so-formed diastereomer is separated by fractional crystallization or chromatography methods well known in the art, and then the pure enantiomer is recovered.

The term "solvate" refers to a composite material or a polymer made up of one or more molecules of a compound in formula I or a pharmaceutically acceptable salt thereof and one or more molecules of a solvent. This solvate is normally a crystal of solute and solvent with a fixed molar ratio. Representative solvents include, such as, ethanol, acetic acid, isopropanol, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the invention.

The term "therapeutically effective amount" refers to an amount sufficient to achieve treatment by administering to a patient in need of treatment.

The term "leaving group" refers to a functional group or atom substituted with another group or atom in a substitution reaction, such as a nucleophilic substitution reaction. Representative leaving group includes, for example, chlorine, bromine, iodine, etc .; sulfonate groups such as methanesulfonate, p-toluenesulfonate, p-bromobenzenesulfonate, p-nitrobenzenesulfonate, etc .; and acyloxy groups such as acetyloxy, trifluoroacetyloxy, etc.

The term "amino protecting group" refers to an amino group suitable for preventing unnecessary irreversible reaction of the amino group in the reaction process, and the protecting group can then be removed without affecting other parts of the molecular structure. Representative amino protecting groups include, but are not limited to, benzyl (Bn), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, acetyl, etc.

The term "hydroxy protecting group" refers to a suitable protecting group for hydroxy groups to prevent unnecessary reactions from occurring. Representative hydroxy protecting group includes, but is not limited to, silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc .; esters (acyl groups) such as formyl, acetyl, etc .; and arylmethyl groups such as benzyl, p-methoxybenzyl, 9-fluorenylmethyl, benzhydryl, etc. Furthermore, the two hydroxy groups can be protected by protecting groups, such as propylene glycol ether formed by the reaction of acetone and diol.

Detailed description of the preferred embodiment

The following preparation and examples illustrate specific embodiments of the invention, which are not intended to limit the scope of the invention in any way, unless otherwise specified.

Preparation 1

(R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-benzylaminoethanol

(a) 4-Hydroxy-3-chloromethylacetophenone

360 g (2.637 mol) of 4-hydroxyacetophenone was placed in a 5000 mL three-necked flask, 775.5 g (10.34 mol) of aqueous formaldehyde solution was added and 3216 g of concentrated hydrochloric acid was added with stirring. . The solid was completely dissolved, the temperature of the reaction mixture was set to be 20 ° C by a cold water bath, and HCl was introduced. The reaction continued with stirring, the reaction solution turned red and the solid precipitated. The reaction continued with stirring for 5 hours. The reaction mixture was poured into ice water, stirred for 30 minutes, filtered to collect the solid, washed with water 5 times, 1000 mL each, and then washed with petroleum ether 2 times. The solid was dried in an oven at 50 ° C to obtain 400 g of 4-hydroxy-3-chloromethylacetophenone red solid in 82.1% yield.

(b) 4-hydroxy-3-acetyloxymethylacetophenone

397.5 g (2.153 moles) of 4-hydroxy-3-chloromethylacetophenone was placed in a 2000 mL three-neck flask, 1000 mL of glacial acetic acid was added and 215 g (2.62 moles) of sodium acetate were added. with agitation. The reaction mixture was heated to 100 ° C, the reaction solution was brown, the reaction continued with stirring at this temperature for 3 hours and the reaction was terminated. The reaction was cooled to room temperature. The reaction mixture was poured into ice water, and extracted 3 times with dichloromethane, 600 mL each time. The organic phase was combined and washed 3 times with water. The organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered and removed. Dichloromethane was removed under reduced pressure. The residual solid was dissolved with 200 mL of ethyl acetate under heating, cooled, and crystallized. The solid was filtered and collected to obtain 211 g of 4-hydroxy-3-acetyloxymethylacetophenone as a white solid in a yield of 47%.

(c) 4-Benzyloxy-3-acetyloxymethylacetophenone

315 g (1.51 mol) of 4-hydroxy-3-acetyloxymethylacetophenone was placed in a 3000 mL three-necked flask and 1800 mL of DMF (N, N-dimethylformamide) was added for dissolution. The reaction was cooled to the internal temperature of 10 ° C, 215 g of anhydrous potassium carbonate was added, 291 g (1.65 mol) of benzyl bromide was added dropwise at this temperature, and the addition dropwise it was completed in 2 hours. The temperature of the reaction mixture increased to 30 ° C, and the reaction continued for 10 hours. Potassium carbonate was filtered off and N, N-dimethylformamide was removed under reduced pressure from the solution. 1500 mL of water was added to the residue, and it was extracted with ethyl ether 3 times, 1000 mL each time. The ethyl ether extract solution was combined. The ethyl ether phase was washed 3 times with water, 1000 mL each time, and the ethyl ether phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the ethyl ether was removed. The residue was dissolved by heating with 150 mL of ethanol, and allowed to cool for crystallization. The solid was filtered and collected to obtain 334 g of 4-benzyloxy-3-acetyloxymethylacetophenone as a white solid in 74% yield.

(d) 4-Benzyloxy-3-hydroxymethylacetophenone

238 g (0.798 mol) of 4-benzyloxy-3-acetyloxymethylacetophenone was placed in a 3000 mL three-necked flask, 1900 mL of methanol was added, and the starting materials were dissolved by heating and stirring. Then 83.11 g (1.995 mol) of sodium hydroxide was added. The reaction was heated and refluxed for 1 hour. The reaction was stopped, the solvent was removed under reduced pressure, 1000 mL of water was added, and the mixture was extracted 3 times with dichloromethane, 800 mL each time. The dichloromethane phases were combined and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off. The solution was concentrated under reduced pressure. A part of the dichloromethane was removed, then the same volume of ethyl acetate was added, and the solution was placed in a refrigerator for crystallization. The solid was filtered and collected to obtain 172.56 g of 4-benzyloxy-3-hydroxymethylacetophenone as a white solid in 84.4% yield.

(e) 4-Benzyloxy-3-benzyloxymethylacetophenone

172.56 g (0.673 mol) of 4-benzyloxy-3-hydroxymethylacetophenone was dissolved in 1000 mL of tetrahydrofuran placed in a 2 L three-necked flask, and heated to the internal temperature of 30 ° C. Sodium hydride was added in batches, total 34.65 g (1.0 mol). After the addition, the reaction continued with stirring for 20 minutes, and benzyl bromide 176.28 g (1.0 mol) was added dropwise at this temperature over about 1 hour. After the addition, the reaction continued with stirring for 10 hours. The solvent was removed under reduced pressure. 800 mL of water was added to the residue, and it was extracted 3 times with ethyl acetate, 600 mL each time. The extracted solutions were combined, dried over anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure after removing the desiccant by filtration. The residue was dissolved with ethanol for crystallization, and the solid was filtered and collected to obtain 164.15 g of white 4-benzyloxy-3-benzyloxymethylacetophenone with a yield of 70.4%.

(f) 4-Benzyloxy-3-benzyloxymethylbromoacetophenone

178.5 g (500.1 mmol) of 4-benzyloxy-3-benzyloxymethylacetophenone was placed in a 3 L three-necked flask. 2200 mL of dichloromethane was added and stirred for 30 min. 88 g (510 mmol) of bromine was added dropwise at the internal temperature of 20-25 ° C. The dropwise addition was completed in 2 hours, and the reaction was carried out for 30 min, so that a large amount of solid products was obtained. TLC analysis showed that the starting materials were slightly unreacted completely. The solid was removed by filtration. The solid was dissolved in a mixed solvent of 2000 mL of dichloromethane, and washed with saturated aqueous sodium bicarbonate solution (1000 mL x 3 times). The organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was consumed under reduced pressure (20 ° C) by a water pump to obtain a solid. The solid was recrystallized from absolute ethanol, and cooled to dryness to obtain 180.5 g of the product in 83.1% yield.

(g) (R) -1 - [(4-Benzyloxy-3-benzyloxymethyl) phenyl] -2-bromoethanol

0.360 g (2.37 mmol) of (1R, 2S) - (+) - 1-amino-2-indenol was placed in a 2 L three-necked flask. 145 mL of THF was added and stirred at 20- 25 ° C. 3.3 mL (34.8 mmol) of borane-dimethyl sulfide was added and stirred for 20 min, at the same time 130.72 g (300.0 mmol) of 4-benzyloxy-3-benzyloxymethylbromoacetophenone in 1396 mL of THF solution and 24.54 mL (258, 8 mmol) of borane-dimethyl sulfide in 364 mL of THF solution. The dropwise addition was completed in 3 hours. The reaction was kept at a temperature of 20-25 ° C and reacted for 30 min under nitrogen protection. TLC analysis showed the reaction to be complete. With external ice bath cooling (<10 ° C), 145.4 mL of methanol was added dropwise, and the reaction was kept in an ice bath (<10 ° C) and stirred for 10 minutes after adding dropwise. The solvent was consumed at 40 ° C under reduced pressure by a water pump. 500 mL of water and 500 mL of ethyl acetate were added and stirred at room temperature until bubbles were generated. The solution was stirred at room temperature for 5 minutes, and transferred to a separatory funnel. The aqueous phase was separated, the aqueous phase was further extracted with ethyl acetate (150 mLx3 times). The organic phases were combined and dried over anhydrous magnesium sulfate.

The desiccant was filtered off, and the solvent was consumed at 40 ° C under reduced pressure by a water pump to obtain a crude product. 113.1 g of oily viscous product was obtained by crude column chromatography in 86.0% yield.

1H NMR (ppm): (CDaCl), 7.52-7.38 (5H), 7.36-7.29 (5H), 7.27-7.19 (2H), 6.88 (d, 1H ), 5.19 (s, 2H), 5.10 (s, 2H), 4.92 (t, 1H), 3.86-3.79 (m, 1H), 3.66-3.52 ( m, 1H), 2.18 (Br, 1H) Hp LC analysis (chiral column, Daicel AD-H column, 4.6mm * 250mm), 96.831% (R configuration), 2.54% (S configuration ).

(h) (R) -1 - [(4-Benzyloxy-3-benzyloxymethyl) phenyl] -2-benzylaminoethanol

87.4 g (200.0 mmol) of intermediate (R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-bromoethanol was placed in a 500 mL three-neck flask. 162.3 g (1.517 moles) of benzylamine and 100 mL of dioxane were added. The reaction was carried out for 3 hours at 100-110 ° C in an oil bath. Analysis by c Cf showed that the intermediate product reacted completely. The solvent was removed at 45 ° C under reduced pressure by a water pump. 500 mL of ethyl acetate and 500 mL of water were added and stirred, sodium bicarbonate was added

aqueous phase with pH 8-9, the aqueous phase was transferred to a separatory funnel to separate the organic phase, and the aqueous phase was further extracted with ethyl acetate (300 mLx3 times). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed at 45 ° C under reduced pressure by a water pump to obtain an oily product.

160 mL of ethyl acetate was added to the aforementioned oily product, stirred to dissolve, cooled, and crystallized in an ice bath. The white solid was filtered off and washed with a small amount of ethyl acetate. The product was dried in air at 60 ° C for 2 hours to obtain 64.8 g of crystallized product with a reaction yield of 75.5%.

1H NMR (ppm, DMSO (ds)): 7.52-7.38 (5H), 7.36-7.09 (10H), 7.27-7.19 (2H), 6.88 (d, 1H), 5.19 (s, 2H), 5.10 (s, 2H), 4.92 (t, 1H), 3.86-3.79 (m, 1H), 3.66-3.52 (m, 1H), 2.18 (Br, 1H)

Preparation 2

(R) - (-) - 3 - [(R) -2-Hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane

(a) R-cyclopentylmandelic acid

In a 5 L three-necked flask, 320 g (1.453 mol) of cyclopentylmandelic acid racemate, 2670 mL of acetonitrile and 211 mL of water were added, stirred and heated to dissolve. The temperature of the reaction mixture was 40-45 ° C, at which time the solid dissolved completely. 141.53 g (0.725 mol) of D-tyrosine methyl ester was added at this temperature to precipitate a solid. Heating was carried out until the reaction mixture was refluxed and the solid dissolved completely so that a clear and transparent solution was obtained. Heating was stopped, the reaction mixture was cooled to 0 ° C in an ice bath, and the reaction continued with stirring for 4 hours to precipitate a large amount of crystals. The solid was collected by filtration, washed with acetonitrile three times (3x150 mL) and dried to obtain 230.69 g of R-cyclopentylmandelic acid D-tyrosine methyl ester salt in 76.6% yield.

230.69 g of the above R-cyclopentylmandelic acid D-tyrosine methyl ester salt was added to a 5 L three-necked flask, and 2000 mL of toluene and 1000 mL of water were added. 66 mL of concentrated hydrochloric acid was added with stirring, heated to 40 ° C in a water bath until the solid was completely dissolved, and cooled. The aqueous phase and the organic phase were separated with a separatory funnel. 20 mL of concentrated hydrochloric acid was added to the aqueous phase and it was extracted twice (2x250 mL) with toluene. The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed under reduced pressure, and 500 mL of n-hexane was added to the residue and stirred to produce a large amount of solid. The solid was filtered and dried at 45 ° C for 3 hours to obtain 134.4 g of white R-cyclopentylmandelic acid solid in 83.4% yield.

(b) (R) -2-Hydroxy-2-phenyl-2-cyclopentylethanol

In a 10 L reaction kettle, 134 g (0.608 mol) of R-cyclopentylmandelic acid and 2 L of glycol dimethyl ether were added and stirred to dissolve. The reaction mixture was cooled to -5 ° C, 243.21 g (1.824 mol) of aluminum trichloride was added slowly, the temperature was maintained, 92 g (2.43 mol) of sodium borohydride was added in batches and the addition was completed in half an hour. The temperature of the reaction mixture increased to 50 ° C, and the reaction was continuously stirred for 4 hours. After completion of the reaction, the mixture was cooled to about 10 ° C and 1.1 L of 2 mol / L hydrochloric acid was added dropwise to check that the temperature of the reaction mixture did not change. After the addition was complete, isopropyl ether was used to extract 3 times (3x500 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution 3 times (3x200 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed under reduced pressure, petroleum ether was added to triturate the residue, and the solid was filtered and collected to obtain 99.88 g of (R) -2-hydroxy-2-phenyl -2-cyclopentylethanol with a yield of 79.6%.

(c) (R) -2-Hydroxy-2-phenyl-2-cyclopentylethanol p-Toluenesulfonate

350 mL of dichloromethane was placed in a 2 L three-necked flask. 98.88 g (0.479 mole) of (R) -2-hydroxy-2-phenyl-2-cyclopentylethanol was added and stirred to dissolve. The reaction mixture was cooled to -5 ° C, 121.17 g (1.198 mol) of N-methylmorpholine was added and 400 mL of dichloromethane solution containing 91.32 g (0.479 mol) of chloride was added dropwise. of paratoluenesulfonyl. The dropwise addition was completed in 1 hour, and the reaction continued at this temperature for 4 hours. The reaction mixture was washed 3 times with water (3x500 mL) to separate the organic phase, and the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed under reduced pressure, isopropyl ether was added to triturate the residue, and the solid was filtered and collected to obtain 140 g of (R) -2-hydroxy-2- p-toluenesulfonate. phenyl-2-cyclopentylethanol with a yield of 81.1%.

(d) (R) -1-Phenyl-1-cyclopentyl-ethylene oxide

700 mL of dimethyl sulfoxide was placed in a 2 L three-necked flask, 139 g (0.386 mol) of (R) -2-hydroxy-2-phenyl-2-cyclopentylethanol ptoluenesulfonate was added, the temperature of the mixture reaction increased to 30 ° C, and the solid dissolved completely with stirring. 20.07 g (0.502 mol) of solid sodium hydride (60%) was added. After the addition, the temperature of the reaction mixture increased to 50 ° C and the reaction continued for 3 hours, the starting materials completely disappeared. The reaction solution was cooled to 10 ° C, 300 mL of water was added dropwise, and isopropyl ether was added to extract three times (3x500 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 70 g of solid (R) -1-phenyl-1-cyclopentyl-ethylene oxide in 96.3% yield.

(e) (R) - (-) - 3 - [(R) -2-Hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane

500 mL of dimethyl sulfoxide was placed in a 2 L reaction kettle. 47.5 g (0.373 mole) of R - (-) - 3-quinine alcohol was added and stirred, but the solid was insoluble. 7.5 g (0.313 mol) of sodium hydride (60%) was added until bubbles were generated. The reaction mixture was heated to 80 ° C, and the reaction was stirred at this temperature for 1 hour. 100 mL of dimethyl sulfoxide solution containing 70 g (0.372 mol) of (R) -1-phenyl-1-cyclopentyl-ethylene oxide was added dropwise over about 1 hour. After the addition was complete, the reaction continued at this temperature for 2 hours. The reaction mixture was cooled to 20 ° C, and 785 mL of water was added dropwise. The addition was completed, the mixture was extracted 3 times with ethyl acetate (3x500 mL), the organic phases were combined, and the organic phases were washed 3 times with water (3x200 mL). The organic phases were separated and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 88.5 g of solid (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy- 1-azabicyclo [2.2.2] octane in 75.2% yield.

Preparation 3

8-Benzyloxy-5 - [(R) -2-benzylamino-1-hydroxyethyl] -1 H-quinolin-2-one

(a) 8-Acetyloxy- (1 H) -quinolin-2-one

80 g (0.5 mole) of 8-hydroxyquinoline nitrogen oxide was added to a 500 mL three-necked flask. 300 mL (3.15 mol) of acetic anhydride was added, stirred and heated to 90-100 ° C. The reaction continued with stirring for 4 hours while maintaining said temperature, and the reaction mixture was cooled in an ice bath to precipitate a solid. The solid was collected by filtration, washed with ice cold acetic anhydride twice (2x50 mL), and dried in vacuo to obtain 82.2 g of 8-acetyloxy- (1H) -quinolin-2-one solid with a yield of 81.0%.

(b) 5-Acetyl-8-hydroxy- (1 H) -quinolin-2-one

In a 500 mL three-necked flask, 200 mL of 1,2-dichloroethane was added, then 61 g (0.30 mol) of 8-acetyloxy- (1H) -quinolin-2-one was added to suspend in a solvent, the reaction mixture was heated to 80 ° C, 120 g (0.90 mol) of aluminum trichloride was added in batches and the reaction continued at this temperature for 1.5 hours to fully convert it to 5-acetyl-8-hydroxy- (1H) -quinolin-2-one. Then, the reaction mixture was poured into 1 liter of hot water with 80 ° C, and was kept at this temperature for 30 minutes. Then, the reaction mixture was thermally filtered. The solid was ground, washed with water, and dried under vacuum at 80 ° C. 50.3 g of light yellow 5-acetyl-8-hydroxy- (1H) -quinolin-2-one were obtained with a yield of 82.6%.

(c) 5-Acetyl-8-benzyloxy- (1 H) -quinolin-2-one

32.52 g (0.16 mol) of 5-acetyl-8-hydroxy- (1 H) -quinolin-2-one was added to a 500 mL reaction flask, 200 mL of N, N-dimethylformamide was added For dissolution, 27.2 g (0.20 mol) of anhydrous potassium carbonate was added, 27.4 g (0.16 mol) of benzyl bromide was added dropwise with stirring, and the reaction was stirred at room temperature for 4 hours. Potassium carbonate was filtered off. The residue was dissolved in 1500 mL of dichloromethane, washed 3 times with water (3x300 mL), and dried over anhydrous magnesium sulfate. The dichloromethane was filtered off and concentrated, the residue was ground with acetone, and the solid was filtered and washed with acetone / water (1/1, 2x35 mL) obtaining 42.8 g of 5-acetyl-8-benzyloxy. (1H) -quinolin-2-one in 91.5% yield.

(d) 8-Benzyloxy-5-bromoacetyl- (1 H) -quinolin-2-one

40.0 g (0.137 mol) of 5-acetyl-8-benzyloxy- (1H) -quinolin-2-one was added to a 1-liter three-necked flask and 500 mL of dichloromethane was added and stirred to dissolve. . The reaction solution was cooled to about 0 ° C in an ice bath, and 0.267 g (0.002 mol) of anhydrous aluminum trichloride was added. Then 20 g (0.15 mol) of bromine was added dropwise, the addition was completed in about 30 minutes, and the reaction mixture was raised to room temperature. At this temperature, the reaction continued with stirring for 4 hours, and detection by thin layer chromatography showed that the reaction was complete. The reaction mixture was washed with saturated sodium bicarbonate solution three times (3x100 mL), and the organic phase was dried over anhydrous magnesium sulfate for 3 hours. The magnesium sulfate was removed by filtration, and the solvent was removed by concentrating under reduced pressure, obtaining 42.2 g of solid 8-benzyloxy-5- (2-bromoacetyl) - (1H) -quinolin-2-one with a yield 82.9%.

(e) 8-Benzyloxy-5 - [(R) -2-bromo-1-hydroxyethyl] -1 H-quinolin-2-one

0.12 g (0.79 mmol) of (1 R, 2S) - (+) - 1-amino-2-indenol was placed in a 500 mL three-neck flask. 50 mL of THF was added and stirred at 20-25 ° C. 1.1 mL (11.6 mmol) of borane-dimethyl sulfide was added and stirred for 20 min. At the same time, 37.2 g (100.0 mmol) of 8-benzyloxy-5- (2-bromoacetyl) - (1H) -quinolin-2-one were added dropwise at 20-25 ° C over 3 hours. and 500 mL of THF solution and 8.1 mL (86.3 mmol) of borane-dimethyl sulfide and 120 mL of THF solution. The reaction was kept at a temperature of 20-25 ° C and reacted for 30 min under nitrogen protection. TLC analysis showed the reaction to be complete. With external ice bath cooling (<10 ° C), 50 mL of methanol was added dropwise, and the reaction was kept in the ice bath (<10 ° C) and stirred for 10 minutes after the addition. drop by drop. The solvent was removed below 45 ° C under reduced pressure by a water pump. 200 mL of water and 200 mL of ethyl acetate were added and stirred at room temperature until bubbles were generated, stirred at room temperature for 5 minutes, and transferred to a separatory funnel. The aqueous phase was separated. The aqueous phase was further extracted with ethyl acetate (50 mLx3 times). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed below 45 ° C under reduced pressure by a water pump to obtain a crude product. The crude product was thermally dissolved with 400 mL of acetonitrile. 3 g of activated carbon was added. Reflux was carried out for 5 minutes, filtration was carried out when hot, and the crystals were precipitated by cooling. The solid was filtered and collected, obtaining 31.8 g of 8-benzyloxy-5 - [(R) -2-bromo-1-hydroxyethyl] -1 H-quinolin-2-one in a yield of 85.5%.

(f) 8-Benzyloxy-5 - [(R) -2-benzylamino-1-hydroxyethyl] - (1 H) -quinolin-2-one

29.9 g (80.0 mmol) of intermediate 8-benzyloxy-5 - [(R) -2-bromo-1-hydroxyethyl] - (1H) -quinolin-2-one was placed in a three neck flask 500 mL. 40.3 g (0.51 mole) of benzylamine and 30 mL of dioxane were added. The reaction was carried out for 3 hours at 100-110 ° C in an oil bath. TLC analysis showed that the intermediate reacted completely. The solvent was removed below 45 ° C under reduced pressure by a water pump. 150 mL of ethyl acetate and 200 mL of water were added and stirred, sodium bicarbonate was added to adjust the aqueous phase to pH 8-9, the aqueous phase was transferred to a separating funnel to separate the organic phase, and further extracted the aqueous phase with ethyl acetate (100 mLx3 times). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was removed below 45 ° C under reduced pressure by a water pump to obtain an oily product.

160 mL of ethyl acetate was added to the oily product from above and stirred to dissolve, cooled, and crystallized in an ice bath. The white solid was filtered off and washed with a small amount of ethyl acetate. The product was dried in air at 60 ° C for 2 hours, obtaining 25 g of crystalline product with a reaction yield of 81.2%.

Preparation 4

(R) -2-Benzylamino-1 - [(4-benzyloxy-3-formamido) phenyl] ethanol

(a) (R) -2-Bromo-1 - [(4-benzyloxy-3-nitro) phenyl] ethanol

0.132 g (0.87 mmol) of (1R, 2S) - (+) - 1-amino-2-indenol was placed in a 2 L three-necked flask. 180 mL of THF was added, and stirred at approximately 10 ° C. 9.2 mL (97.0 mmol) of borane-dimethyl sulfide was added and stirred for 25 min. The temperature of the reaction mixture was kept at 5-10 ° C, at the same time, 63.6 g (180.16 mmol) of 4-benzyloxy-3-nitro-bromoacetophenone and 600 mL of solution were added dropwise of THF and 8.1 mL (86.3 mmol) of borane-dimethyl sulfide and 120 mL of THF solution. The dropwise addition was completed in 3 hours. The reaction mixture was kept at 5-10 ° C and reacted for 30 min under nitrogen protection. TLC analysis showed the reaction to be complete. With external ice bath cooling (<10 ° C), 50 mL of methanol was added dropwise, and the reaction was kept in an ice bath (<10 ° C) and stirred for 10 minutes after the addition. drop by drop. The solvent was pumped out at 45 ° C under reduced pressure by a water pump. 200 mL of water and 200 mL of ethyl acetate were added to the residue, stirred at room temperature until bubbles were generated, stirred at room temperature for 5 minutes, and transferred to a separatory funnel. The aqueous phase was separated. The aqueous phase was further extracted with ethyl acetate (100 mLx3 times). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was consumed below 45 ° C under reduced pressure by a water pump to obtain an oily product. The oily product was ground with n-hexane and cooled to separate the solid. The solid was filtered and collected, obtaining 57.9 g of (R) -2-bromo-1 - [(4-benzyloxy-3-nitro) phenyl] ethanol with a yield of 90.5%.

(b) (R) -2-Bromo-1 - [(4-benzyloxy-3-amino) phenyl] ethanol

55 g (156.15 mmol) of (R) -2-bromo-1 - [(4-benzyloxy-3-nitro) phenyl] ethanol was placed in a 1 L hydrogenation reaction kettle. 600 mL of methanol, stirred and dissolved. After that, 5 g of 10% palladium-carbon was added, hydrogen was introduced, the pressure was kept at 0.4 MPa, and the reaction temperature was kept not to be higher than 5 ° C. Under these conditions, the reaction was carried out for 12 hours. The reaction mixture was filtered. Palladium-carbon was washed with methanol three times (3x100 mL) and the solvent was removed under reduced pressure. The residue was dissolved with ethyl acetate / petroleum ether (1/1), cooled and crystallized at 0 ° C, filtered to collect the solid and dried obtaining 41.9 g of (R) -2-bromo- 1 - [(4-benzyloxy-3-amino) phenyl] ethanol in 83.3% yield.

(c) (R) -2-Bromo-1 - [(4-benzyloxy-3-formylamino) phenyl] ethanol

In a 500 mL three-necked flask, 88 g of anhydrous formic acid was added, cooled to 0-5 ° C. 19.6 g (18.7 mmol) of acetic anhydride was added dropwise with stirring, the reaction temperature was kept at 0-5 ° C, the reaction solution was stirred for 15 minutes, 40.0 g was added (12.4 mmol) of (R) -2-bromo-1 - [(4-benzyloxy-3-amino) phenyl] ethanol to the reaction solution, and the reaction continued at this temperature for 10 hours, so that the starting material (R) -2-bromo-1 - [(4-benzyloxy-3-amino) phenyl] ethanol reacts completely. Excess formic acid was removed under reduced pressure. The residue was dissolved with 400 mL of dichloromethane. The dichloromethane phase was washed with water three times (3x100 mL). The organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off. The solvent was removed under reduced pressure. The residue was dissolved with 300 mL of methanol by heating, cooling was carried out for crystallization, and the solid was filtered and collected, obtaining 30.2 g of (R) -2-bromo-1 - [(4-benzyloxy-3- formylamino) phenyl] ethanol in a yield of 72.8%.

(d) (R) -2-Benzylamino-1 - [(4-benzyloxy-3-formylamino) phenyl] ethanol

30.0 g (85.7 mmol) of intermediate (R) -2-bromo-1 - [(4-benzyloxy-3-formylamino) phenyl] ethanol was added to a 500 mL three-necked flask with 40, 3 g (0.51 mol) of benzylamine and 30 mL of dioxane. The reaction was carried out for 3 hours at 100-110 ° C in an oil bath. TLC analysis showed that the intermediate reacted completely. The solvent was consumed under reduced pressure (45 ° C, -0.095 MPa) by a water pump. 250 mL of ethyl acetate and 200 mL of water were added and stirred, sodium bicarbonate was added to adjust the aqueous phase to pH 8-9, and the aqueous phase was transferred to a separatory funnel to separate the organic phase. The aqueous phase was further extracted with ethyl acetate (100 mLx3 times). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed below 45 ° C under reduced pressure by a water pump to obtain an oily product.

260 mL of ethyl acetate was added to the aforementioned oily product and stirred to dissolve, cooled and crystallized in an ice bath. The white solid was filtered off and washed with a small amount of ethyl acetate. The product was dried in air at 60 ° C for 2 hours, obtaining 19.65 g of crystalline product with a reaction yield of 80.1%.

Preparation 5

8 - [(1 R) -1-Hydroxy-2-benzylamine] ethyl-5-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one (formula 28)

(a) 2-Hydroxy-5-benzyloxy acetophenone

152 g (1.0 mol) of 2,5-dihydroxyacetophenone was added to a 1 L three-necked flask. 400 mL of absolute ethanol was added, stirred to dissolve. 92.4 g (1.1 mol) of sodium bicarbonate was added at room temperature and stirred for 5 minutes. The temperature of the reaction mixture was kept at 0-10 ° C. 180 g (1.05 mol) of benzyl bromide was added dropwise, and the addition was complete in 20 minutes. At this temperature, the reaction continued with stirring for 3 hours, and thin-layer detection showed that the starting material 2,5-dihydroxyacetophenone reacted completely. The solvent was removed under reduced pressure. The residue was dissolved with 400 mL of dichloromethane, and washed with saturated aqueous citric acid solution 3 times (3x150 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed by filtration. The dichloromethane was removed from the solution under reduced pressure. The residue was dissolved in 300 mL of absolute ethanol which was cooled and crystallized, obtaining 213.7 g of 2-hydroxy-5-benzyloxyacetophenone as a white solid with a yield of 88.3%. Chemical purity was 99.0% (HPLC).

(b) 2-Hydroxy-3-nitro-5-benzyloxy acetophenone

210 g (0.868 mol) of 2-hydroxy-5-benzyloxyacetophenone and 900 mL of glacial acetic acid were added to a 2 L three-necked flask for dissolution, the reaction mixture was cooled to 10-20 ° C, 64.3 mL (0.90 mol) of 63% concentrated nitric acid was added dropwise and the addition was complete in 20 minutes. The reaction continued stirring at this temperature for 1 hour, and the reaction was complete. The reaction mixture was poured into 900 mL of ice water, and stirred continuously for 1 hour to precipitate the crystals. The solid was filtered, washed with ice water three times and dried under vacuum at 50 ° C, obtaining 224 g of 2-hydroxy-3-nitro-5-benzyloxyacetophenone solid with a yield of 89.9%. Chemical purity was 99.2% (HPLC).

(c) 2-Hydroxy-3-amino-5-benzyloxyacetophenone

220 g (0.767 mol) of 2-hydroxy-3-nitro-5-benzyloxyacetophenone solid was placed in a 2 L hydrogenation reaction kettle, 800 mL of dioxane was added and 11 g of platinum oxide was added. At room temperature, hydrogen was introduced and the pressure was kept at 3 MPa until the absorption of hydrogen stopped. The catalyst was filtered off and used directly for the next reaction without treatment.

(d) 8-Acetyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one

272 g (2.0 mol) of anhydrous potassium carbonate was added to a 3 L three-necked flask, and the filtrate from step (c) above was added and stirred. 112.5 g (0.90 mol) of chloroacetyl chloride dissolved in 800 mL of dioxane was added dropwise at room temperature, and the addition was completed in 30 minutes. The reaction mixture was heated to 70 ° C and the reaction continued stirring for 2 hours. The solvent was removed under reduced pressure, 1 L of water was added to the residue, and it was dissolved with 1 L of dichloromethane. The aqueous phase was extracted to separate the organic phase. The aqueous phase is extracted with dichloromethane twice (2x500 mL). The organic phases were combined, and washed with water three times (3x500 mL). The organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off. A part of dichloromethane was removed under reduced pressure until a volume of the organic phases was approximately 500 mL. Adding 1500 mL of petroleum ether and stirring, the organic phases precipitated crystals. The crystals were filtered and dried at 50 ° C obtaining 156.7 g of solid 8-acetyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one with a total yield of 68.8% in two stages. Chemical purity was 99.1% (HPLC).

(e) 8- (Bromoacetyl) -6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one

148.5 g (0.50 mol) of 8-acetyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one solid was added to a 2-liter three-necked flask, and added 1000 mL of dioxane and stirred to dissolve. The reaction solution was cooled to about 0 ° C in an ice bath, and 1.0 g (0.01 mol) of anhydrous aluminum trichloride was added. Then 176 g (0.55 mol) of bromine was added dropwise, and the addition was complete in about 30 minutes. The reaction mixture rose to room temperature. At this temperature, the reaction continued with stirring for 4 hours, and detection thin layer chromatography showed that the reaction was complete. The solvent was removed from the reaction mixture under reduced pressure. The residue was dissolved in 1000 mL of dichloromethane, and washed with saturated sodium bicarbonate solution three times (3x100 mL). The organic phase was dried over anhydrous magnesium sulfate for 3 hours. Magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure to remove solvent, and the oily product obtained was ground with petroleum ether to obtain 161.2 g of solid 8- (bromoacetyl) -6-benzyloxy-2H -1,4-benzoxazin-3 (4H) -one with a yield of 85.7%. Chemical purity was 98.3% (HPLC).

(f) 8 - [(1 R) -1-Hydroxy-2-bromo] ethyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one

0.308 g (2.61 mmol) of (1R, 2S) - (+) - 1-amino-2-indenol was placed in a 3 L three-necked flask. 380 mL of THF was added and stirred at approximately 10 ° C. 21.4 mL (0.226 mole) of borane-dimethyl sulfide was added and stirred for 25 min. The temperature of the reaction mixture was kept at 5-10 ° C, at the same time, 158.2 g (0.42mol) of solid 8- (bromoacetyl) -6-benzyloxy-2H-1 was added dropwise , 4-benzoxazin-3 (4H) -one in 1200 mL of THF solution and 18.9 mL (0.20 mole) of borane-dimethyl sulfide in 120 mL of THF solution, and the dropwise addition was completed in 3 hours. The reaction mixture was kept at 5-10 ° C and reacted for 30 min under nitrogen protection. TLC analysis showed the reaction to be complete. With external ice bath cooling (<10 ° C), 120 mL of methanol was added dropwise, and the reaction mixture was kept in an ice bath (<10 ° C) and stirred for 10 minutes after adding dropwise. The solvent was removed below 45 ° C under reduced pressure by a water pump. 500 mL of water and 500 mL of ethyl acetate were added to the residue and it was stirred at room temperature until bubbles were generated. The mixture was stirred at room temperature for 5 min and transferred to a separatory funnel to separate the organic phase. The aqueous phase was further extracted with ethyl acetate (100 mLx3 times), the organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed below 45 ° C under reduced pressure by a water pump to obtain an oily product. The oily product was ground with nhexane and cooled to precipitate a solid. The solid was filtered and collected to obtain 144.5 g of 8 - [(1 R) -1-hydroxy-2-bromo] ethyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one with a yield of 91.0%. The chemical purity is 98.5% (HPLC) and the ee value is 95%.

(g) 8 - [(1 R) -1-Hydroxy-2-benzylamine] ethyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one

143.6 g (0.38 mol) of intermediate (8 - [(1R) -1-hydroxy-2-bromo] ethyl-5-benzyloxy-2H-1,4-benzoxazin-3 (4H) - one in a 1000 mL three-necked flask. 321.0 g (3.0 moles) of benzylamine and 120 mL of dioxane were added. The reaction was carried out for 3.5 h at 100-110 ° C in a bath of oil. Analysis by TLC showed that the intermediate product reacted completely. The solvent was consumed under reduced pressure (45 ° C, -0.095 MPa) by a water pump. 1050 mL of dichloromethane and 400 mL of water were added and stirred, sodium bicarbonate was added

decantation to separate the organic phase. The aqueous phase was further extracted with dichloromethane (200 mLx3 times). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed below 45 ° C under reduced pressure by a water pump to obtain an oily product.

460 mL of ethyl acetate was added to the aforementioned oily product and stirred to dissolve. The reaction mixture was cooled and crystallized in an ice bath. The white solid was filtered off and washed with a small amount of ethyl acetate. The product was dried in air at 60 ° C for 2 hours, obtaining 123.6 g of crystallized product of 8 - [(1R) -1-hydroxy-2-benzylamine] ethyl-6-benzyloxy-2H-1,4-benzoxazin -3 (4H) -one with a reaction yield of 83.6%. The purity of the isomer was 98.5%.

Example 1

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {3 - [(R) -2- (3-hydroxymethyl-4-) bromide hydroxy) phenyl-2-hydroxyethylamino] propyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (3-bromopropyl) -1 -azabicyclo [2,2, 2] octylonium

In a 250 mL three-necked flask, 30 mL of absolute ethanol and 6.0 g (19.02 mmol) of (R) - (-) - 3 - [(R) -2-hydroxy-2- cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane (Preparation 2), stirred and dissolved, and then 153.6 g (760.8 mmol) of 1,3-dibromopropane was added , stirred and reacted at room temperature for 12 hours. Ethanol and excess 1,3-dibromopropane were removed under reduced pressure and the residue was crystallized with dichloromethane and n-hexane (1/2) obtaining 9.5 g of (R) - (-) - 3 bromide solid - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (3-bromopropyl) -1-azabicyclo [2,2,2] octylonium in 96.1% yield. e M (m / z) 436.3, 438.3.

(b) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(R) -2- (3-benzyloxymethyl) bromide -4-benzyloxy) phenyl-2-hydroxyethylbenzylamino] propyl} -1-azabicyclo [2,2,2] octylonium

2.396 g (5.283 mmol) of (R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-benzylaminoethanol (Preparation 1) and 2.733 g (5.283 mmol) of (a) were added to a flask of 50 mL reaction. 20 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.475 g (10.566 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 80 ° C, and the reaction was carried out at this temperature for 5 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped, and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. Solvent was removed From the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 3.0 g of the target product. The yield was 63.8%. MS (m / z) 809.9.

(c) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(R) -2- (3-hydroxymethyl) bromide -4-hydroxy) phenyl-2-hydroxyethylamino] propyl} -1-azabicyclo [2,2,2] octylonium

2.5 g (4.83 mmol) of the product (b) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.5 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 10 hours, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from ethanol. 1.6 g of the objective solid compound was obtained in a yield of 53.5%. 1H NMR (5 ppm) (DMSO-d6) 7.19-7.24 (m, 5H), 6.95-7.01 (m, 3H), 5.0 (s, 1H), 4.80 (s, 2H), 4.74 (m, 1H), 3.93 (s, 2H), 3.68 (d, 2H), 3.15 (m, 1H), 2.90 (m, 1H) , 2.84 (m, 1H), 2.55 (m, 2H), 2.43 (S, 1H), 2.36 (m, 2H), 2.21 (s, 1H), 2.10 ( s, 1H), 2.0 (m, 3H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.56-1 , 60 (m, 6H), 1.34-1.46 (m, 6H); Calcd for C32H4 / BrN2O5 MS (m / z): 619.63, found: 539.27 (M-Br). Example 2

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (3 - {(R) - [2-hydroxy-2- (8 -hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propyl) -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (3-bromopropyl) -1 -azabicyclo [2,2, 2] octylonium The above compound was prepared according to the method of Example 1 (a).

(B) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (3 - {(R) - [2-hydroxy-2 bromide - (8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylbenzylamino} propyl) -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 1 (b).

2.0 g (5.0 mmol) of 8-benzyloxy-5 - [(R) -2-benzylamino-1-hydroxyethyl] - [1 H) -quinolin-2-one (Preparation 2) and 2.587 g (5.0 mmol) from (a) to a 50 mL reaction flask. 20 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.475 g (10.566 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 80 ° C. The reaction was carried out at this temperature for 5 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 2.3 g of the target product. The yield was 54.9%. MS (m / z) 758.65.

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (3 - {(R) - [2-hydroxy-2 - (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propyl) -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 1 (c).

2.2 g (2.62 mmol) of the product (b) was placed in a hydrogenation reaction kettle, 20 mL of methanol was added for the solution, 0.4 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 10 hours, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.3 g of the objective solid compound was obtained in a yield of 90.0%.

1H NMR (5 ppm) (DMSO-ds) 8.0 (s, 1H), 7.36 (d, 1H), 7.19-7.24 (m, 5H), 6.71 (d, 1H) 6.57 (d, 1H), 6.52 (d, 1H), 5.01 (s, 1H), 4.79 (s, 2H), 4.73 (m, 1H), 3, 93 (s, 2H), 3.68 (d, 2H), 3.15 (m, 1H), 2.90 (m, 1H), 2.84 (m, 1H), 2.54 (m, 2H ), 2.43 (S, 1H), 2.36 (m, 2H), 2.10 (s, 1H), 2.0 (m, 3H), 1.79-1.82 (m, 3H) , 1.75 (m, 1H), 1.68 (m, 2H), 1.55-1.61 (m, 6H), 1.35-1.46 (m, 6H). Calculated for C34H46BrN3O5 MS (m / z): 656.65, found: 576.26 (M-Br).

Example 3

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {4 - [(R) -2- (3-hydroxymethyl-4-) bromide hydroxy) phenyl-2-hydroxyethylamino] butyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (4-bromobutyl) -1 -azabicyclo [2,2, 2] octylonium

The above compound was prepared according to the method of Example 1 (a).

In a 250 mL three-necked flask, 25 mL of absolute ethanol and 0.5 g of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] were added. ethoxy-1-azabicyclo [2.2.2] octane (15.85 mmol) (Preparation 2), stirred and dissolved. Then 78.4 mL (634.0 mmol) of 1,4-dibromobutane was added, stirred and reacted at room temperature for 18 hours. Ethanol and excess 1,4-dibromobutane were removed under reduced pressure and the residue was crystallized with dichloromethane and n-hexane (1/2) obtaining 8.1 g of (R) - (-) - 3 bromide solid - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (4-bromobutyl) -1-azabicyclo [2,2,2] octylonium in 96.1% yield. MS (m / z) 450.3, 452.3.

(b) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {4 - [(R) -2- (3-benzyloxymethyl) bromide -4-benzyloxy) phenyl-2-hydroxyethylbenzylamino] butyl} -1-azabicyclo [2,2,2] octylonium

4.096 g (7.253 mmol) of (R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-benzylaminoethanol (Preparation 1) and 3.854 g (7.253 mmol) of (a) were added to a flask of 50 mL reaction. 30 mL of N, N-dimethylformamide was added. After the reaction mixture was stirred for 10 minutes, 3.038 g (21.759 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 55-60 ° C, and the reaction was carried out there. temperature for 12 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 3.24 g of the target product. The yield was 48.0%. MS (m / z) 823.811.

(c) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {4 - [(R) -2- (3-hydroxymethyl) bromide -4-hydroxy) phenyl-2-hydroxyethylamino] butyl} -1-azabicyclo [2,2,2] octylonium

2.8 g (3.11 mmol) of product (b) was placed in a hydrogenation reactor kettle, 30 mL of methanol was added for the solution, 0.7 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 12 hours, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from ethanol. 1.5 g of the objective solid compound was obtained in a yield of 76.5%. 1H NMR (5 ppm) (DMSO-d6) 7.18-7.23 (m, 5H), 6.96-7.01 (m, 3H), 5.0 (s, 1H), 4.80 (s, 2H), 4.74 (m, 1H), 3.93 (s, 2H), 3.68 (d, 2H), 3.15 (m, 1H), 2.90 (m, 1H) , 2.83 (m, 1H), 2.55 (m, 2H), 2.43 (s, 1H), 2.35 (m, 2H), 2.21 (s, 1H), 2.10 ( s, 1H), 2.0 (m, 3H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.55-1 , 61 (m, 8H), 1.34-1.46 (m, 6H); calculated for MS (m / z) of Caa ^ gBrNaOa: 633.66, found: 553.38 (M-Br).

Example 4

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (4 - {(R) - [2-hydroxy-2- (3) -formamido-4-hydroxy) phenyl] ethylamino} butyl-1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (4-bromobutyl) -1-azabicyclo [2,2, 2] octylonium

The above compound was prepared according to the method of Example 3 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (4 - {(R) - [2-hydroxy-2 - (3-formamido-4-benzyloxy) phenyl] ethylbenzylamino} butyl-1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 3 (b).

1.882 g (5.0 mmol) of (R) -2-benzylamino-1 - [(4-benzyloxy-3-formamido) phenyl] ethanol (Preparation 4) and 2.66 g (5.0 mmol) of (a) To a 50 mL reaction flask, 30 mL of acetonitrile was added. After the reaction mixture was stirred for 10 minutes, 1.5 g (11.0 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 55-60 ° C, and the reaction was carried held at this temperature for 12 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of ethanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 3.04 g of the target product. The yield was 73.6%. MS (m / z) 746.911.

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (4 - {(R) - [2-hydroxy-2 - (3-formamido-4-hydroxy) phenyl] ethylamino} butyl-1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 3 (c).

2.9 g (3.42 mmol) of the product (b) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.6 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 15 hours, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from ethanol. 1.5 g of the objective solid compound was obtained in a yield of 67.8%. 1H NMR (5 ppm) (DMSO-d6) 8.21 (s, 1H), 7.40 (m, 1H), 7.18-7.23 (m, 5H), 6.66-6.71 ( m, 2H), 5.0 (s, 1H), 4.74 (m, 1H), 4.0 (s, 1H), 3.92 (s, 2H), 3.68 (d, 2H), 3.15 (m, 1H), 2.91 (m, 1H), 2.83 (m, 1H), 2.54 (m, 2H), 2.42 (S, 1H), 2.35 ( m, 2H), 2.10 (s, 1H), 2.0 (m, 3H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.69 (m , 2H), 1.55-1.61 (m, 8H), 1.34-1.46 (m, 6H); calculated for C33H4sBrN3O5 M (m / z): 646.65, found: 566.28.

Example 5

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9 - {- [(R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} nonyl) -1-azabicyclo [2,2,2] octylonium

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9 - {- [(R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} nonyl) -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9-bromononyl) -1 -azabicyclo [2,2, 2] octylonium

The above compound was prepared according to the method of Example 1 (a).

In a 250 mL three-necked flask, 35 mL of absolute ethanol and 5.0 g (15.85 mmol) of (R) - (-) - 3 - [(R) -2-hydroxy-2- were added cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane (Preparation 2), stirred and dissolved. Then 60.69 g (212.2 mmol) of 1,9-dibromononane was added, stirred and reacted at room temperature for 18 hours. Ethanol and excess 1,9-dibromononane were removed under reduced pressure and the residue was crystallized with dichloromethane and petroleum ether (1/3) to obtain 9.1 g of the objective product with a yield of 95.4%. MS (m / z) 520.18, 522.18.

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1-9 - {(R) - [2-hydroxy-2- (5-benzyloxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylbenzylamino} nonyl) -1-azabicyclo [2,2,2] octylonium

2.02 g (5.0 mmol) of 8 - [(1R) -1-hydroxy-2-benzylamine] ethyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one (Preparation 5) and 3.0 g (5.0 mmol) from (a) to a 50 mL reaction flask, 30 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.0 g (7.35 mmol) of anhydrous potassium carbonate was added. The temperature of the reaction mixture increased to 65-70 ° C. The reaction was carried out at this temperature for 12 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for lyophilization by freezing, and the solid was filtered and collected to obtain 3.56 g of the target product. The yield was 77.0%. MS (m / z) 844.35 (M-Br).

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9 - {- [(R) - [2-hydroxy -2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} nonyl) -1-azabicyclo [2,2,2] octylonium

3.4 g (3.67 mmol) of the product (b) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.6 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 15 hours of reaction, hydrogen absorption was stopped, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.5 g of the objective solid compound was obtained in a yield of 54.8%. H NMR (5 ppm) (DMSO-d6) 8.0 (s, 1H), 7.15-7.20 (m, 5H), 6.60 (d, 1H), 6.20 (d, 1H) , 5.0 (s, 1H), 4.88 (s, 2H), 4.73 (m, 1H), 3.93 (s, 1H), 3.68 (d, 1H), 3.14 (m, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.55 (m, 2H), 2.36 (m, 2H), 2.21 (s, 1H) , 2.10 (s, 1H), 2.0 (m, 2H), 1.96 (m, 1H), 1.79-1.80 (m, 3H), 1.75 (m, 1H) , 1.69 (m, 2H), 1.55-1.61 (m, 6H), 1.34-1.46 (m, 10H), 1.27-1.29 (m, 10H); Calcd for C39H5sBrN3O6 MS (m / z): 744.80, found: 664.35 (M-Br).

(d) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (9 - {- [(R) - [2-hydroxy -2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} nonyl) -1-azabicyclo [2,2,2] octylonium

0.56 g (0.75 mmol) of product (c) was dissolved in 10 mL of methanol-water (v / v 1: 1), 0.10 g of silver oxide was added, it was stirred at room temperature for 30 minutes, the resulting solid was filtered off, the solid was washed with 5 mL of water, the filtrates were combined, concentrated under reduced pressure to remove part of the solvent, 82 mg of methanesulfonic acid was added, stirred for 10 minutes , 0.2 g of active carbon was added to the solution, it was stirred continuously for 5 minutes, it was filtered, the filtrate was concentrated to dryness and the residue was crystallized with 3 mL of isopropanol obtaining 0.45 g of the objective product, with a 59.2% yield. Elemental analysis for C ⁴⁰ H ⁶¹ N ³ O ⁹ S (%) (calculated value) C63.10 (63.21), H7.97 (8.09), N5.36 (5.53).

The following compounds can be synthesized using similar methods and starting materials described above.

Preparation 6

4-Tert-butoxyformylamino-1-butanol

318 g (3.0 moles) of sodium carbonate were placed in a 3 L three-necked flask. 500 mL of dioxane and 500 mL of water were added and dissolved. 178 g (2.0 mol) of 4-amino-1-butanol was added to the reaction flask once, and stirred uniformly. The temperature of the reaction mixture was maintained at about 10 ° C, and 500 mL of dioxane solution containing 545 g (2.50 moles) of di-tert-butyl dicarbonate was added dropwise. The reaction temperature was maintained and stirring continued for 4 hours. Dioxane was removed under reduced pressure. The aqueous phase was extracted with dichloromethane three times (3x1000 mL), dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure, obtaining 343 g of the objective product with a yield of 90.7%. Preparation 7

4-tert-butoxyformylaminobutyl-2-bromoethyl ether

In a 500 mL three-necked flask, 37.8 g (0.20 mol) of 4-tert-butoxyiformylamino-1-butanol was added and dissolved in 200 mL of tetrahydrofuran. 8.0 g (0.20 mol) of sodium hydride (60%) was added, stirred for 15 minutes. 75.2 g (0.40 mol) of 1,2-dibromoethane was added dropwise. After the addition, the temperature of the The reaction mixture rose to 50 ° C, and the reaction continued for 4 hours. The solvent and excess 1,2-dibromoethane were removed under reduced pressure. The residue was dissolved in 300 mL of ethyl acetate, washed with water three times (3x100 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 48.5 g of the target product in a 77.2% yield.

Example 25

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- [2- (4 - {(R) - [2-hydroxy-2 - (3-formamido-4-hydroxy) phenyl] ethylamino} butoxy) ethyl] -1-azabicyclo [2,2,2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4-tert-butoxyformamidobutoxy) ethyl] -1 bromide -azabicyclo [2,2,2] octylonium

In a 250 mL three-necked flask, 25 mL of absolute ethanol and 5.0 g (15.85 mmol) of (R) - (-) - 3 - [(R) -2-hydroxy-2- cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane (Preparation 2), stirred and dissolved. Then 16.2 g (50.0 mmol) of 4-tert-butoxyformylaminobutyl-2-bromoethyl ether (Preparation 7) was added, stirred and reacted at room temperature for 24 hours. Ethanol was removed under reduced pressure and the residue was crystallized from dichloromethane and n-hexane (2/1) to obtain 6.1 g of solid target product in 63.1% yield. MS (m / z) 531.3 (M-Br).

(b) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4-aminobutoxy) ethyl] -1-azabicyclo bromide [2,2,2] octylonium

5.9 g (8.92 mmol) of product (a) was placed in a 50 mL single-neck flask. 30 mL of 2 moles of HBr-dioxane solution was added, stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the remaining solid was neutralized with N-methylmorpholine and subjected to column chromatography to obtain 3.3 g of the target product in a yield of 72.3%. MS (m / z) 431.3 (M-Br).

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4 - {(R) - [2- hydroxy-2- (3-formamido-4-benzyloxy) phenyl] ethylamino} butoxy) ethyl] -1-azabicyclo [2,2,2] octylonium

3.20 g (9.39 mmol) of intermediate (R) -2-bromo-1 - [(4-benzyloxy-3-formylamino) phenyl] ethanol (Preparation 4) was placed in a three-neck flask of 50 mL. 3.20 g (6.26 mmol) of (b), 2.76 g (20 mmol) of anhydrous potassium carbonate and 5 mL of dioxane were added. The reaction was carried out in an oil bath at 100-110 ° C for 3 hours. TLC analysis showed that the intermediate reacted completely. The solvent was consumed under reduced pressure by a water pump (45 ° C, -0.095 MPa). The residue was ground with a mixed solvent of petroleum ether and dichloromethane (3/1) to obtain a solid. The solid crystallized with isopropanol obtaining 3.8 g of the objective product with a 77.7% yield. MS (m / z) 700.3 (M-Br)

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} butoxy) ethyl] -1-azabicyclo [2,2,2] octylonium

3.50 g (4.48 mmol) of product (c) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.5 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 10 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from ethanol. 1.8 g of the objective solid compound was obtained in a 58.2% yield. 1H NMR (5 ppm) (DMSO-d6) 8.20 (s, 1H), 7.40 (m, 1H), 7.18-7.23 (m, 5H), 6.64-6.71 ( m, 2H), 5.0 (s, 1H), 4.74 (m, 1H), 4.0 (s, 1H), 3.93 (s, 1H), 3.67 (d, 1H), 3.37-3.47 (m, 4H), 3.15 (m, 1H), 2.91 (m, 1H), 2.83 (m, 1H), 2.53-2.55 (m, 4H), 2.25 (m, 2H), 2.10 (s, 1H), 1.96-2.0 (m, 3H), 1.75-1.81 (m, 3H), 1.69 (m, 2H), 1.56-1.60 (m, 6H), 1.34-1.46 (m, 6H); Calcd for C35H52BrN3Os MS (m / z): 690.71, Found: MS (m / z) 610.30 (M-Br).

Preparation 8

4-Tert-butoxyformamidebutyl-5-bromopentyl ether

The above compound was prepared according to the method of Preparation 7.

Preparation 9

4-Tert-butoxyformamidebutyl-4-bromobutyl ether

The above compound was prepared according to the method of Preparation 7.

Preparation 10

4-Tert-butoxyformamidebutyl-3-bromopropyl ether

The above compound was prepared according to the method of Preparation 7.

Preparation 11

2-Tert-butoxyformamideethyl-2-bromoethyl ether

The above compound was prepared according to the method of Preparation 7.

Example 26

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4 - {(R) - [2-hydroxy-2 - (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butoxy) pentyl] -1-azabicyclo [2,2,2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4-tert-butoxyfomiamidobutoxy) pentyl] -1 bromide -azabicyclo [2,2,2] octylonium

In a 250 mL three-necked flask, 25 mL of absolute ethanol and 5.0 g (15.85 mmol) of (R) - (-) - 3 - [(R) -2-hydroxy-2- cyclopentyl-2-phenyl] ethoxy-1 -azabicyclo [2,2,2] octane (Preparation 2), stirred to dissolve. Then 17.58 g (52.0 mmol) of 4-tert-butoxyformamidobutyl-5-bromopentyl ether (Preparation 8) was added. The reaction mixture was stirred to react at 40 ° C for 4 hours. The ethanol was removed under reduced pressure and the residue was crystallized from dichloromethane and n-hexane (2/1) to obtain 6.0 g of the solid objective product in a yield of 60.1%. MS (m / z) 573.3 (M-Br).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4-aminobutoxy) pentyl] -1 -azabicyclo [2,2,2] octylonium

5.9 g (9.02 mmol) of product (a) was placed in a 50 mL single-neck flask, and 30 mL of 2 moles of HBr-dioxane solution was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the remaining solid was neutralized with N-methylmorpholine and subjected to column chromatography to obtain 3.2 g of the target product in 64.2% yield. e M (m / z) 473.3 (M-Br).

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4 - {(R) - [2- hydroxy-2- (6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butoxy) pentyl] -1-azabicyclo [2,2,2] octylonium

4.20 g (11.2 mmol) of intermediate 8 - [(1R) -1-hydroxy-2-bromo] ethyl-5-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one was introduced (Preparation 5 (f)) in a 50 mL three-necked flask. 3.10 g (5.60 mmol) of (b), 2.76 g (20 mmol) of potassium carbonate and 5 mL of dioxane were added. The reaction was carried out in an oil bath at 100-110 ° C for 3 h. TLC analysis showed that the intermediate reacted completely. The solvent was consumed below 45 ° C under reduced pressure by a water pump. The residue was ground with a mixed solvent of petroleum ether and dichloromethane (3/1) to obtain a solid. The solid crystallized with isopropanol to obtain 3.9 g of the objective product with a yield of 81.8%. MS (m / z) 770.4 (M-Br).

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4 - {(R) - [2- hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butoxy) pentyl] -1-azabicyclo [2,2,2] octylonium

3.80 g (4.47 mmol) of the product (c) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.5 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 10 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.9 g of the objective solid compound was obtained in a yield of 55.8%. 1H NMR (5 ppm) (DMSO-ds) 8.0 (s, 1H), 7.18-7.20 (m, 5H), 6.65 (d, 1H), 6.20 (d, 1 H), 5.0 (s, 1H), 4.88 (s, 2H), 4.74 (m, 1H), 3.93 (d, 1H), 3.68 (d, 1H), 3.37-3.40 (m, 4H), 3.15 (m, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.55 (m, 2H), 2 , 36 (t, 2H), 2.10 (s, 1H), 1.98-2.0 (m, 3H), 1.75 1.81 (m, 4H), 1.69 (m, 2H), 1.56-1. 60 (m, 6H), 1.34-1.46 (m, 12H), 1.29 (m, 2H); Calcd for C39H58BrN3O7 MS (m / z): 760.80, Found: MS (m / z) 680.35 (M-Br).

Example 27

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- [4- (4 - {(R) - [2- (3- hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} butoxy) butyl-1-azabicyclo [2,2,2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [4- (4-tert-butoxyformamidobutoxy) butyl-1 - bromide azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 25 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [4- (4-aminobutoxy) butyl-1 -azabicyclo [ 2,2,2] octylonium

The above compound was prepared according to the method of Example 25 (b).

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- [4- (4 - {(R) - [2- (3-benzyloxyhydroxymethyl-4-benzyloxy) phenyl-2-hydroxy] ethylamino} butoxy) butyl-1-azabicyclo [2,2,2] octylonium

3.50 g (8.19 mmol) of intermediate (R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-bromoethanol (Preparation 1 (g)) was placed in a three-neck flask of 50 mL. 3.20 g (5.09 mmol) of (b), 2.76 g (20 mmol) of potassium carbonate and 5 mL of dioxane were added. The reaction was carried out for 3 hours at 100-110 ° C in an oil bath. Analysis by c Cf showed that the intermediate product reacted completely. The solvent was consumed below 45 ° C under reduced pressure by a water pump. The residue was ground with a mixed solvent of petroleum ether and dichloromethane (3/1) to obtain a solid. The solid crystallized with isopropanol obtaining 4.1 g of the objective product with a yield of 93.8%. MS (m / z) 777.4 (M-Br).

(d) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [4- (4 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} butoxy) butyl-1-azabicyclo [2,2,2] octylonium

4.0 g (4.10 mmol) of the product (c) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.8 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 20 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from ethanol. 1.6 g of the objective solid compound was obtained in a yield of 55.4%. 1H NMR (5 ppm) (DMSO-d6) 7.17-7.20 (m, 5H), 6.95 (m, 2H), 6.64 (d, 1H), 5.0 (s, 1H) , 4.79 (s, 2H), 4.74 (m, 1H), 3.93 (d, 1H), 3.67 (d, 1H), 3.37-3.47 (t, 4H), 3.14 (m, 1H), 2.90 (m, 1H), 2.84 (m, 1H), 2.53-2.55 (m, 2H), 2.36 (m, 2H), 1 , 96-2.0 (m, 5H), 1.74-1.81 (m, 4H), 1.69 (m, 2H), 1.56-1.60 (m, 6H), 1.34 -1.46 (m, 14H); Calcd for C37H57BrN2O6 MS (m / z): 705.76, found: 625.34 (M-Br).

The following compounds can be prepared from the above starting materials according to the above methods.

Preparation 12

1,3-Bis (2-bromoethoxy) propane

38 g (0.50 mol) of 1,3-propanediol was dissolved in 500 mL of tetrahydrofuran. 40 g (1.0 mol) of sodium hydride (60%) was added. The reaction mixture was stirred at room temperature for 15 minutes. 752 g (4.0 mol) of 1,2-dibromoethane was added dropwise. After the addition, the reflux reaction was carried out for 3 hours, the solvent and excess 1,2-dibromoethane were removed under reduced pressure. The residue was dissolved in 500 mL of dichloromethane, washed with water three times (3x200 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 80 g of the target product in a 61% yield.

Preparation 13

Bis (2-bromoethoxyethyl) ether

42.4 g (0.40 mol) of bis (2-hydroxyethyl) ether was dissolved in 400 mL of tetrahydrofuran. 33.6 g (1.05 mol) of sodium hydride (60%) was added. The reaction mixture was stirred at room temperature for 25 minutes. 752 g (4.0 mol) of 1,2-dibromoethane was added dropwise. After the addition, the reflux reaction was carried out for 5 hours, the solvent and excess 1,2-dibromoethane were removed under reduced pressure. The residue was dissolved in 400 mL of dichloromethane, washed with water three times (3x200 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 70 g of the target product in a yield of 54.7%.

Example 45

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (2- {2- [2- (2 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethoxy) ethoxy] ethoxy} ethyl) -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- {2- [2- (2-ethoxy) ethoxy] ethoxy} bromoethyl) -1 -azabicyclo [2,2,2] octylonium

In a 250 mL three-necked flask, 30 mL of absolute ethanol, 6.0 g (19.02 mmol) of (R) - (-) - 3 - [(R) -2-hydroxy-2- cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane (Preparation 2), stirred and dissolved. Then 243.6 g (760.8 mmol) of bis (2-bromoethoxyethyl) ether (Preparation 13) was added. The reaction mixture was stirred to react at room temperature for 10 hours. The ethanol was removed under reduced pressure, the excess bis (2-bromoethoxyethyl) ether in the residue was removed by column chromatography and the crude product crystallized with dichloromethane and n-hexane (1/1) obtaining 9.3 g of the target product with a yield of 76.9%. MS (m / z) 654.2, 656.2.

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- (2- {2- [2- (2 - {( R) - [2- (3-benzyloxymethyl-4-benzyloxy) phenyl-2-hydroxy] ethylamino} ethoxy) ethoxy] ethoxy} ethyl) -1-azabicyclo [2,2,2] octylonium

2.396 g (5.283 mmol) of (R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-benzylaminoethanol (Preparation 1) and 3.46 g (5.283 mmol) of (a) were added to a 50 mL reaction flask. 20 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.475 g (10.566 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 80 ° C, and the reaction was carried out at this temperature for 3 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 2.8 g of the target product. The yield was 57.7%. Calculated for Em (m / z) of C51H69BrN2O8: 918.0, found: 838.4 (M-Br).

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- {2- [2- (2 - {( R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethoxy) ethoxy] ethoxy} ethyl) -1-azabicyclo [2,2,2] octylonium

2.4 g (2.61 mmol) of product (b) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.5 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 20 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. I know obtained 1.3 g of the objective solid compound in a yield of 67.5%. 1H NMR (5 ppm) (DMSO-d6) 7.18-7.21 (m, 5H), 6.59-6.95 (m, 3H), 5.0 (s, 1H), 4.79 ( s, 2H), 4.74 (m, 1H), 3.93 (d, 1H), 3.68 (d, 1H), 3.47-3.54 (m, 12H), 3.15 (m , 1H), 2.90 (m, 1H), 2.83 (m, 1H), 2.72 (t, 2H), 2.53 (m, 2H), 2.36 (m, 1H), 2 , 21 (S, 1H), 2.10 (s, 1H), 1.96-2.0 (m, 3H), 1.79-1.81 (m, 3H), 1.74 (m, 1H ), 1.69 (m, 2H), 1.56-1.60 (m, 6H), 1.33-1.45 (m, 6H); Calcd for C3 / H57BrN2O8 MS (m / z): 737.76, found: 657.3 (M-Br).

Example 46

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {2- [2- (2 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethoxy) ethoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [2- (2-chloroethoxy) ethoxy] ethyl chloride } -1 -azabicyclo [2,2,2] octylonium

In a 250 mL three-necked flask, 30 mL of absolute ethanol, 6.0 g (19.02 mmol) of (R) - (-) - 3 - [(R) -2-hydroxy-2- cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane (Preparation 2), stirred and dissolved. Then 142.3 g (760.8 mmol) of 1,2-bis (2-chloroethoxy) ethane (Shanghai Hanhong Chemical) was added. The reaction mixture was heated to 45 ° C, stirred and reacted for 6 hours. Ethanol was removed under reduced pressure, excess 1,2-bis (2-chloroethoxy) ethane in the residue was removed by column chromatography and the crude product crystallized with dichloromethane and n-hexane (3/1) to obtain 8 , 3g of the target product in 86.8% yield. Calculated for C2sH41ClNO4 MS (m / z): 502.51, found: 466.24 (M-Cl), 468.23 (M-Cl).

(b) Chloride of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [2- (2 - {(R) - [2-hydroxy-2- (3-formamido-4-benzyloxy) phenyl] ethylamino} ethoxy) ethoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

1.882 g (5.0 mmol) of (R) -2-benzylamino-1 - [(4-benzyloxy-3-formamido) phenyl] ethanol (Preparation 4) and 2.568 g (5.0 mmol) of (a ) to a 50 mL reaction flask. 30 mL of acetonitrile was added. After the reaction mixture was stirred for 10 minutes, 1.5 g (11.0 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 75-80 ° C, and the reaction was carried held at this temperature for 8 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 2.4 g of the target product. The yield was 63.8%. Calculated for MS (m / z) of C42H58ClN3O7: 752.38, found: 716.84 (M-Cl).

(c) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [2- (2 - {(R) - chloride) [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethoxy) ethoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

2.1 g (2.79 mmol) of the product (b) was placed in a hydrogenation reaction kettle, 25 mL of methanol was added for the solution, 0.4 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 10 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.1 g of the objective solid compound was obtained in a yield of 59.5%. 1H NMR (5 ppm) (DMSO-ds) 8.20 (s, 1H), 7.40 (dd, 1H), 7.19-7.21 (m, 5H), 6.64-6.76 (m, 2H), 5.01 (s, 1H), 4.73 (m, 1H), 4.0 (s, 1H), 3.93 (d, 2H), 3.68 (d, 2H) , 3.47-3.54 (m, 8H), 3.15 (m, 1H), 2.90 (m, 1H), 2.84 (m, 1H), 2.72 (t, 2H), 2.53 (d, 2H), 2.10 (s, 1H), 2.0 (m, 3H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1 , 68 (m, 2H), 1.55-1.61 (m, 6H), 1.34-1.46 (m, 6H); Calcd ^{for C 35} H ^{52 ClN 3} O ⁷ MS (m / z): 662.26, found: 626.74 (M-Cl).

The following compounds can be prepared from the above starting materials according to the methods of Examples 45 and 46:

Preparation 14

2 - [(4-bromoethoxy) phenyl] ethyl alcohol

(a) 4- [2-Hydroxyethyl] phenol

166 g (1.0 mol) of methyl p-hydroxyphenylacetate was dissolved in 500 mL of methanol, cooled in an ice bath. 56.75 g (1.50 mol) of sodium borohydride was added in batches and the addition was complete in about 2 hours. The reaction continued with stirring for 2 hours. Thin layer detection showed that the starting materials reacted completely. The solvent was removed under reduced pressure. The residue was dissolved in water which was adjusted to be pH 2 by adding 2M hydrochloric acid. The solution was extracted with dichloromethane three times (300 mLx3). The extracts were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed under reduced pressure and the residue was crystallized with ethyl acetate and petroleum ether (1/5). 120.0 g of the objective compound was obtained in a yield of 86.9%.

(b) 2 - [(4-bromoethoxy) phenyl] ethyl alcohol

30 g (0.217 mol) of the product (a) was dissolved in 300 mL of ethanol. 22.4 (0.26 mole) of sodium bicarbonate was added. 188 g (1.0 mol) of 1,2-dibromoethane was added at the same time. The reaction mixture was heated and stirred. The reaction was carried out at 50 ° C for 5 hours. The solvent and excess 1,2-dibromoethane were removed under reduced pressure. The residue was dissolved in 300 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off. The solvent was removed under reduced pressure to obtain 35.0 g of the target compound in a yield of 65.8%. m / z 245.01.247.05 (M + H).

Preparation 15

2 - [(4-bromopropoxy) phenyl] ethyl alcohol

30 g (0.217 mol) of the product of preparation 14 (a) was dissolved in 300 mL of ethanol. 22.4 g (0.26 mole) of sodium bicarbonate was added. 202 g (1.0 mol) of 1,3-dibromopropane was added at the same time. The reaction mixture was heated and stirred. The reaction was carried out at 50 ° C for 6 hours. Solvent and excess 1,2-dibromopropane were removed under reduced pressure. The residue was dissolved in 300 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off. The solvent was removed under reduced pressure to obtain 40 g of the target compound in a 71.1% yield. m / z 259.03, 261.04 (M + H).

Preparation 16

3- (4-Bromopropoxyphenyl) propanol

(a) 4- (3-Hydroxypropyl) phenol

45.0 g (0.25 mol) of methyl p-hydroxyphenylpropionate was dissolved in 200 mL of methanol, cooled in an ice bath. 14.2 g (0.375 mol) of sodium borohydride was added in batches, and the addition was complete in about 1 hour. The reaction continued with stirring at room temperature for 2 hours. Thin layer detection showed that the starting materials reacted completely. The solvent was removed under reduced pressure. The residue was dissolved in water which was adjusted to be pH 2 by adding 2M hydrochloric acid. The solution was extracted with dichloromethane three times (200 mLx3). The extracts were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed under reduced pressure and the residue was crystallized with dichloromethane and petroleum ether (1/5). 32.0 g of the objective compound was obtained in a yield of 84.2%.

(b) 3- (4-Bromopropoxyphenyl) propanol

30 g (0.197 mol) of product (a) was dissolved in 300 mL of ethanol. 22.4 (0.26 mole) of sodium bicarbonate was added. 161.6 g (0.80 mol) of 1,3-dibromopropane was added at the same time. The reaction mixture was heated and stirred. The reaction was carried out at 50 ° C for 5 hours. Solvent and excess 1,3-dibromopropane were removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 25 g of the target compound in 46.5% yield. m / z 273.03, 275.04 (M + H).

Preparation 17

4-bromopropoxybenzyl alcohol

The above compound was prepared according to the method of Preparation 16 (b), the yield was 75.1%, m / z 245.01, 247.0 (M + H).

Preparation 18

1 - (4-Bromopropoxyphenyl) acetone

45 g (0.30 mol) of 1- (4-hydroxyphenyl) acetone was dissolved in 300 mL of ethanol. 62.1 g (0.45 mol) of potassium carbonate was added. 161.6 g (0.80 mol) of 1,3-dibromopropane was added at the same time. The reaction mixture was stirred. The reaction was carried out at room temperature for 5 hours, and the solvent and excess 1,3-dibromopropane were removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 44.8 g of the target compound in 52.5% yield. m / z 285.01, 287.02 (M + H).

Preparation 19

1 - (4-Bromoethoxyphenyl) acetone

The above compound was prepared according to the method of Preparation 18. The yield was 62.3%, m / z 271.03, 273.02 (M + H).

Preparation 20

4-bromopropoxy-3,5-dichlorobenzyl alcohol

(a) Methyl 4-Hydroxy-3,5-dichlorobenzoate

62.1 g (0.30 mol) of 4-hydroxy-3,5-dichlorobenzoic acid was dissolved in 300 mL of methanol. 3 g of p-toluenesulfonic acid was added. The reaction mixture was heated and refluxed for 6 hours. The solvent was removed under reduced pressure. The residue was dissolved in 500 mL of dichloromethane, washed with water three times (200 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed, yielding 56.3 g of the target product in 84.9% yield. m / z 219.01 (M-H).

(b) 4-hydroxy-3,5-dichlorobenzyl alcohol

56 g (0.253 mol) of (a) was dissolved in 300 mL of methanol, cooled in an ice bath. 15.13 g (0.40 mol) of sodium borohydride was added in batches, and the addition was complete in about 1.5 hours. The reaction continued with stirring for 2 hours, thin layer detection showed that the starting materials reacted completely. The solvent was removed under reduced pressure. The residue was dissolved in water which was adjusted to be pH 2 by adding 2M hydrochloric acid. The solution was extracted with dichloromethane three times (200 mLx3). The extracts were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed under reduced pressure and the residue was crystallized with dichloromethane and petroleum ether (1/5). 30.3 g of the objective compound was obtained in 62.0% yield. m / z 192.02 (M-H).

(c) 4-bromopropoxy-3,5-dichlorobenzyl alcohol

The above compound was prepared according to the method of Preparation 16 (b), the yield was 68.5%, m / z 311.03 (M-H).

Preparation 21

4- (3-Bromopropoxy) acetophenone

40.8 g (0.30 mol) of 4-hydroxyacetophenone was dissolved in 400 mL of methanol. 62.1 g (0.45 mol) of potassium carbonate was added. 161.6 g (0.80 mol) of 1,3-dibromopropane was added at the same time. The reaction mixture was stirred. The reaction was carried out at room temperature for 10 hours. Solvent and excess 1,3-dibromopropane were removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 44.8 g of the target compound in a 58.1% yield. m / z 257.01, 259.01 (M + H).

Preparation 22

2- (4-Bromopropoxyphenyl) -2-propanol

(a) 2- (4-Benzyloxyphenyl) -2-propanol

62.3 g (0.25 mole) of 4-benzyloxybromobenzene was dissolved in 300 mL of tetrahydrofuran. 6.3 g (0.263 mol) of magnesium metal was added under the protection of argon. A catalytic amount of iodine was added. The reaction mixture was heated and refluxed for 30 minutes. 58 g (1 mol) of acetone was added dropwise. After the addition, the reflux reaction continued for 3 hours. The reaction mixture was cooled to room temperature. While cooling in an ice bath, 132 mL of 2M hydrochloric acid was added dropwise, and Tetrahydrofuran and excess acetone were removed under reduced pressure. The remaining aqueous phase was extracted 3 times with ethyl ether (200 mLx3) and dried over anhydrous magnesium sulfate overnight. The desiccant was filtered off and the filtrate was concentrated to dryness to obtain 38.8 g of the target product in a 68.0% yield. m / z 228.11.

(b) 2- (4-Hydroxyphenyl) -2-propanol

35 g (0.153 mol) of the product (a) was dissolved in 150 mL of methanol, 2.4 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 4 hours of reaction, the reaction was stopped, the catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain 18.8 g of the target product in a yield of 80.7%. m / z 152.08.

(c) 2- (4-Bromopropoxyphenyl) -2-propanol

(b) 15.8 g (0.104 mole) of the product was dissolved in 200 mL of methanol. 31.1 g (0.225 mol) of potassium carbonate was added. 80.8 g (0.40 mol) of 1,3-dibromopropane was added at the same time. The reaction mixture was stirred. The reaction was carried out at room temperature for 20 hours, and the solvent and excess 1,3-dibromopropane were removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 24.8 g of the target compound in 87.3% yield. m / z 272.04, 274.0.

Preparation 23

4- (3-Bromopropoxy) propionylbenzene

The above compound was prepared according to the method of Preparation 22 (c), the yield was 65.8%, m / z 270.02, 272.02.

Preparation 24

1- [4- (2-Bromoethoxy) phenyl] -2-methyl-2-propanol

(a) 1 - [(4-benzyloxy) phenyl] -2-methyl-2-propanol

131.50 g (0.50 mol) of 4-benzyloxybenzyl bromide was dissolved in 600 mL of tetrahydrofuran. 12.6 g (0.526 mol) of magnesium metal was added under the protection of argon. A catalytic amount of iodine was added. The reaction mixture was stirred at room temperature for 30 minutes. 116 g (2.0 mol) of acetone was added dropwise. After the addition, the reaction continued with stirring at room temperature for 4 hours. The reaction mixture was cooled with an ice bath, 266 mL of 2M hydrochloric acid was added dropwise, and tetrahydrofuran and excess acetone were removed under reduced pressure. The remaining aqueous phase was extracted 3 times with dichloromethane (400 mLx3) and dried over anhydrous magnesium sulfate overnight. The desiccant was filtered off and the filtrate was concentrated to dryness to obtain 91.2 g of the target product in a yield of 75.28%. m / z 242.31.

(b) 1 - [(4-Hydroxy) phenyl] -2-methyl-2-propanol

88.0 g (0.363 mol) of product (a) was dissolved in 400 mL of methanol, 4.4 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0, 43 MPa and the temperature was room temperature. After 5 hours of reaction, the reaction was stopped, the catalyst was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was crystallized with dichloromethane / petroleum ether (1: 1) to obtain 53.4 g of the target product in a yield of 88.6%. m / z 166.1.

(c) 1 - [4- (2-Bromoethoxy) phenyl] -2-methyl-2-propanol

20.8 g (0.125 mol) of product (b) was dissolved in 200 mL of methanol. 31.1 g (0.225 mol) of potassium carbonate was added. 75.2 g (0.40 mol) of 1,2-dibromoethane was added at the same time. The reaction mixture was stirred, heated to 50 ° C to react for 20 hours, and filtered. The solvent and excess 1,2-dibromoethane were removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 21.9 g of the target compound in a yield of 80.3%. m / z 272.04, 274.0.

Preparation 25

1- [4- (2-Bromopropoxy) phenyl] -2-methyl-2-propanol

The above compound was prepared according to the method of Preparation 24 (b), the yield was 78.9%, m / z 286.05, 288.0.

Preparation 26

3-Methyl-4- (3-bromopropoxy) acetophenone

30.38 g (0.20 mol) of 4-hydroxy-3-methylacetophenone was dissolved in 300 mL of methanol. 31.1 g (0.225 mol) of potassium carbonate was added. At the same time 121.2 g (0.60 mol) of 1,3-dibromopropane was added. The reaction mixture was stirred and reacted at room temperature for 20 hours. Solvent and excess 1,3-dibromopropane were removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane, washed with water three times (100 mLx3), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure to obtain 28.3 g of the target compound in 52.2% yield. m / z 270.02, 272.0.

Preparation 27

3-Methoxy-4- (3-bromopropoxy) acetophenone

The above compound was prepared according to the method of Preparation 26, the yield was 65.8%, m / z 286.02, 288.0.

Preparation 28

(R) - (-) - 3 - [(R) -2-Benzyloxycarboxyl-2-cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane

31.45 g (0.10 mol) of the (e) product of Preparation 2 was dissolved in 300 mL of dichloromethane, cooled in an ice bath. 20.0 g of triethylamine was added with stirring over 5 minutes. The reaction temperature was controlled to be below 10 ° C. 20.40 g (0.12 mol) of benzyloxyformyl chloride was added dropwise. The reaction was carried out at this temperature for 4 hours. The reaction mixture was filtered. The filtrate was diluted with 200 mL of dichloromethane, washed with saturated sodium bicarbonate solution three times (200 mLx3) and dried over anhydrous magnesium sulfate. A portion, approximately 350 mL, of the solvent was removed under reduced pressure. By adding 200 mL of petroleum ether, the filtrate was cooled and crystallized, obtaining 40.50 g of the objective compound with a yield of 90.1%. MS 449.26.

Example 57

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1- {2- [4- (2 - {[(R) - [ 2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

(R) - (-) - 3 - [(R) -2-Hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2 - {(R) - [2 - (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl)] ethoxy-1 - [2- (4-hydroxyethylphenoxy) ethyl] -1 - azabicyclo [2,2,2] octylonium

In a 250 mL three-necked flask, 30 mL of absolute ethanol and (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl] ethoxy-1-azabicyclo were added. [2,2,2] octane (Preparation 28), stirred and dissolved. Then 69.9 g (285.3 mmol) of (4-bromoethoxy) phenylethyl alcohol (Preparation 14) was added. The reaction mixture was stirred and reacted at room temperature for 12 hours. Ethanol was removed under reduced pressure, excess (4-bromoethoxy) phenethyl alcohol in the residue was removed by column chromatography and the crude product was crystallized with dichloromethane and n-hexane (2/1) obtaining 20.61 g of the target product with a yield of 75.4%. MS (m / z) 614.23.

(b) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - [2- (4-methylsulfonyloxyethylphenoxy) ethyl] -1 - azabicyclo [2,2,2] octylonium

19.3 g (31.4 mmol) of (a) product was dissolved in 150 mL of dichloromethane. 5.0 g (50.0 mmol) of N-methylmorpholine was added. The reaction mixture was cooled in an ice bath. 5.50 g (48.0 mmol) of methylsulfonyl chloride was added dropwise. The reaction continued stirring at this temperature for 4 hours. The solvent was removed under reduced pressure and 18.8 g of the objective product was obtained by column chromatography in a yield of 87.8%, MS (m / z) 682.21.

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1- {2- [4- (2 - {[(R ) - [2- (3-benzyloxymethyl-4-benzyloxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

2.396 g (5.283 mmol) of (R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-benzylaminoethanol (Preparation 1) and 3.57 g (5.283 mmol) of (b) were added to a 50 mL reaction flask. 20 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.475 g (10.566 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 80 ° C, and the reaction was carried out at this temperature for 5 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure. 5 mL of isopropanol was added to the residue for freeze lyophilization and the solid was filtered and collected to obtain 2.85 g of the target product. The yield was 51.87%. Calculated for MS (m / z) C ⁶¹ H ⁶¹ BrN ² O ⁸ : 1040.0, found: 959.4 (M-Br).

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2 - {[(R ) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

2.60 g (2.50 mmol) of the product (c) was placed in a hydrogenation reaction kettle, 18 mL of methanol was added for the solution, 0.5 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 24 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.2 g of the objective solid compound was obtained in a yield of 66.0%. 1H NMR (5 ppm) (DMSO-d6) 7.19-7.21 (m, 5H), 7.01 (d, 2H), 6.59-6.95 (m, 5H), 5.0 ( s, 1H), 4.79 (s, 2H), 4.74 (m, 1H), 4.04 (t, 2H), 3.93 (d, 1H), 3.68 (d, 1H), 3.15 (m, 1H), 2.67-2.90 (m, 8H), 1.96-2. 0 (m, 5H), 1.79-1.81 (m, 3H), 1.74 (m, 1H), 1.69 (m, 2H), 1.56-1.60 (m, 6H) , 1.34-1.45 (m, 6H); calculated for C39H53BrN2O6 M (m / z): 725.75, found: 645.32 (M-Br).

(e) (R) - (-) - 3 - [(R) -2-Hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2 - {(R) benzoate) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

0.545 g (0.75 mmol) of product (d) was dissolved in 50 mL of water, adsorbed and eluted with a strong alkaline anion exchange column. The eluent was concentrated to 50 mL under reduced pressure. 2 mL of ethanol solution containing 100 mg of benzoic acid was added to the reaction mixture, stirred for 5 minutes, and concentrated to dryness under reduced pressure. The residue crystallized from isopropanol. 0.42 g of the objective product was obtained in a yield of 72.9%. Elemental analysis (%) (calculated value) C 71.98 (72.04), H 7.52 (7.62), N 3.61 (3.65).

Example 58

(R) - (-) - 3 - [(R) -2-Hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - [2- hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl)] ethoxy-1 - [3- (4-hydroxymethylphenoxy) propyl] -1 - azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - [3- (4-methylsulfonyloxymethylphenoxy) propyl] -1 - azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (b).

(c) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - [2-hydroxy-2- (8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

2.0 g (5.0 mmol) of 8-benzyloxy-5 - [(R) -2-benzylamino-1-hydroxyethyl] - (1 H) -quinolin-2-one (Preparation 2) and 3 were added, 20 g (5.0 mmol) from (b) to a 50 mL reaction flask. 20 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.475 g (10.566 mmol) of anhydrous potassium carbonate was added. The temperature of the reaction mixture increased to 80 ° C. The reaction was carried out at this temperature for 5 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped, and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 2.6 g of the target product. The yield was 52.6%. Calculated for C56H64BrN3Ü8 MS (m / z): 986.89, found: 906.35 (M-Br).

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

2.40 g (2.43 mmol) of product (c) was placed in a hydrogenation reaction kettle, 20 mL of methanol was added for the solution, 0.5 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 15 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.08 g of the objective solid compound was obtained in a 58.2% yield.

1H NMR (5 ppm) (DMSO-d6) 8.01 (s, 1H), 7.35 (d, 1H), 7.19-7.21 (m, 5H), 6.95 (d, 2H) , 6.71 (d, 1H), 6.57-6.65 (m, 3H), 6.52 (d, 1H), 5.01 (s, 1H), 4.74 (m, 1H ), 3.94 (m, 3H), 3.81 (t, 2H), 3.68 (d, 1H), 3.15 (m, 1H), 2.90 (m, 1H), 2.84 (m, 1H), 2.36 (m, 2H), 2.10 (s, 1H), 2.0 (m, 4H), 1.79-1.82 (m, 5H), 1.75 ( m, 1H), 1.68 (m, 2H), 1.56-1.60 (m, 6H), 1.35-1.46 (m, 6H).

Calculated for C41H52BrN3O6 MS (m / z): 762.772, found: 682.30 (M-Br).

Example 59

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(3,5-dichloro-4- (1 - { (R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) phenoxy) propyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {3- [3,5-dichloro-4- ( hydroxymethyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl)] ethoxy-1 - {3- [3,5-dichloro-4- ( methanesulonyloxymethyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (b).

(c) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(3,5-dichloro-4- ( 1 - {(R) - [2-hydroxy-2- (3-formamido-4-benzyloxy) phenyl] ethylamino} methyl) phenoxy) propyl} -1-azabicyclo [2,2,2] octylonium

1.882 g (5.0 mmol) of (R) -2-benzylamino-1 - [(4-benzyloxy-3-formamido) phenyl] ethanol (Preparation 4) and 3.69 g (5.0 mmol) of (b) To a 50 mL reaction flask, 30 mL of acetonitrile was added. After the reaction mixture was stirred for 10 minutes, 1.5 g (11.0 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 65-70 ° C. The reaction was carried out at this temperature for 10 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped, and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 2.92 g of the target product. The yield was 56.6%. Calculated for MS (m / z) of C54H62BrCl2N3Oe: 1031.76, found: 950.27 (M-Br).

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(3,5-dichloro-4- ( 1 - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) phenoxy) propyl} -1-azabicyclo [2,2,2] octylonium

2.80 g (2.71 mmol) of the product (c) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.8 g of 10% of Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 15 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.38 g of the objective solid compound was obtained in a yield of 63.1%. 1H NMR (5 ppm) (DMSO-ds) 8.20 (s, 1H), 7.40 (m, 1H), 7.18-7.21 (m, 5H), 6.84 (d, 2H ), 6.64-6.76 (m, 2H), 5.01 (s, 1H), 4.73 (m, 1H), 4.01 (s, 1H), 3.93 (m, 3H) , 3.81 (d, 2H), 3.68 (d, 1H), 3.15 (m, 1H), 2.90 (m, 1H), 2.83 (m, 1H), 2.36 ( m, 2H), 2.10 (s, 2H), 1.98-2.0 (m, 3H), 1.79-1.81 (m, 5H), 1.75 (m, 1H), 1.69 (m, 2H), 1.55-1.61 (m, 6H), 1.34-1.46 (m, 6H); Calcd for C39H5üBrCl2N3O6 MS (m / z): 807.64, found: 726.22 (M-Br).

Example 60

(R) - (-) - 3 - [(R) -2-Hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) [- 2- hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} isobutyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2-hydroxy-2- methyl) propylphenoxy] ethyl} -1 -azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2-methylsulfonyloxy-2- methyl) propylphenoxy] ethyl} -1 -azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (b).

(c) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformoxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2 - {(R) - [2-hydroxy-2 - [(6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} isobutyl) phenoxy] ethyl} -1-azabicyclo [2,2 , 2] octylonium

2.02 g (5.0 mmol) of 8 - [(1R) -1-hydroxy-2-benzylamine] ethyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one (Preparation 5) and 3.57 g (5.0 mmol) from (b) to a 50 mL reaction flask. 30 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.0 g (7.35 mmol) of anhydrous potassium carbonate was added. The temperature of the reaction mixture increased to 55-60 ° C. The reaction was carried out at this temperature for 10 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped, and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 10 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 2.98 g of the target product. The yield was 58.5%.

Calculated for MS (m / z) of C57H68BrN3Og: 1018.93, found: 938.38 (M-Br).

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenylethoxy] -1 - {2- [4- (2 - {(R) -2 -hydroxy-2 - [(6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} isobutyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octilonium

2.80 g (2.75 mmol) of product (c) was placed in a hydrogenation reaction kettle, 20 mL of methanol was added for the solution, 0.8 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 12 hours of reaction, hydrogen absorption was stopped, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.46 g of the objective solid compound was obtained in a yield of 66.8%. 1H NMR (5 ppm) (DMSO-da) 8.01 (s, 1H), 7.18-7.20 (m, 5H), 7.01 (d, 2H), 6.72 (d, 2H) , 6.65 (d, 1H), 6.20 (d, 1H), 5.01 (s, 1H), 4.87 (s, 2H), 4.74 (m, 1H), 4.04 ( t, 2H), 3.93 (s, 1H), 3.68 (d, 1H), 3.14 (m, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.78 (t, 2H), 2.59 (s, 2H), 2.10 (m, 2H), 2.0 (m, 2H), 1.96 (m, 1H), 1.79-1 , 81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.56-1.60 (m, 6H), 1.34-1.46 (m, 6H ), 1.15 (s, 6H).

Calculated for C42H56BrN3O7 MS (m / z): 794.93, found: 714.33 (M-Br).

Preparation 29

(R) -1 - [(4-Hydroxy-3-hydroxymethyl) phenyl] -2-aminoethanol

44 g (0.10 mol) of the product (g) of Preparation 1 was dissolved in 300 mL of methanol in a hydrogenation reaction kettle, 6.6 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa, hydrogen uptake was stopped after the hydrogenation reaction was carried out at room temperature for 20 hours, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure and the residue crystallized from isopropanol. 15.6 g of the objective solid compound was obtained in a yield of 85.1%. MS (m / z) 182.09 (M-H).

Preparation 30

8-Hydroxy-5 - [(R) -2-amino-1-hydroxyethyl] -1 H-quinolin-2-one

The above compound was prepared according to the method of Preparation 29 using the product (f) of Preparation 3. Preparation 31

(R) -2-Amino-1 - [(4-hydroxy-3-formamido) phenyl] ethanol

The above compound was prepared according to the method of Preparation 29 using the product (d) of Preparation 4.

Preparation 32

8 - [(1 R) -1-Hydroxy-2-amino] ethyl-6-hydroxy-2H-1,4-benzoxazin-3 (4H) -one

The above compound was prepared according to the method of Preparation 29 using the product (g) of Preparation 5. Example 61

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy] -1- {2- [4- (2 - {(R) - [2 -hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4-acetonylphenoxy) ethyl] -1 -azabicyclo [2,2,2] octylonium The above compound was prepared according to the method of Example 57 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy] -1- {2- [4- (2 - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 3 (b).

0.981 g (5.0 mmol) of (R) -2-amino-1 - [(4-hydroxy-3-formamido) phenyl] ethanol (Preparation 31) and 2.86 g (5.0 mmol) of (a) To a 50 mL reaction flask, 50 mL of dichloromethane was added. After the reaction mixture was stirred for 10 minutes, 1.27 g (6.0 mmol) of sodium triacetylborohydride was added, and 1 drop of acetic acid was added for catalysis. The reaction mixture reacted for 24 hours at room temperature, and thin-layer detection showed that the reaction was complete. The reaction was stopped, and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of ethanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 1.56 g of the target product. The yield was 73.6%. 1H NMR (5 ppm) (DMSO-d6) 8.20 (s, 1H), 7.40 (m, 1H), 7.18-7.20 (m, 5H), 7.01 (d, 2H), 6.72 (d, 2H), 6.66-6.71 (m, 2H), 5.0 (s, 1H), 4.74 (m, 1H), 4.04 (t, 2H ), 4.0 (s, 1H), 3.92 (d, 1H), 3.67 (d, 1H), 3.15-3.18 (m, 2H), 2.91 (m, 1H), 2.78 (t, 2H), 2.54 (m, 2H), 2.76-2.51 (dd, 2H), 2.10 (s, 1H), 1.96-2, 0 (m, 4H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.55-1.61 (m, 6H ), 1.34-1.46 (m, 6H), 1.10 (d, 3H); Calcd for C4üH54BrN3O6 MS (m / z): 752.78, found: 671.32 (M-Br).

(c) Preparation of compound 61 -S and compound 61 -R

0.80 g of product (b) was dissolved in 5 mL of methanol, separated and purified with a preparation column, gradient elution was carried out using acetonitrile and mixed water, to collect, respectively, the components 61-S and 61-R, the solvent was removed under reduced pressure and the residue was crystallized with ethanol to obtain 0.28 g of compound (61-S) and 0.31 g of compound (63-R).

Example 62

(R) - (-) - 3 - [(R) -2-Hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - [2- hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [3- (4-propionylphenoxy) propyl] -1-azabicyclo bromide [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

1.27 g (6.0 mmol) of sodium triacetylborohydride was suspended in 50 mL of dichloromethane, 1.10 g (5.0 mmol) of 8-hydroxy-5 - [(R) -2-amino-1 - were added hydroxyethyl] -1 H-quinolin-2-one (Preparation 30) and 3.0 g (5.0 mmol) of (a) and 1 drop of acetic acid was added for catalysis. The reaction continued with stirring for 20 hours at room temperature. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 8 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 2.3 g of the target product. The yield was 58.2%.

1H NMR (5 ppm) (DMSO-d6) 8.01 (s, 1H), 7.36 (d, 1H), 7.19-7.21 (m, 5H), 7.02 (d, 2H) , 6.71 (m, 3H), 6.56 (d, 1H), 6.52 (d, 1H), 5.01 (s, 1H), 4.74 (m, 1H), 3, 94-3. 90 (m, 4H), 3.67 (d, 1H), 3.16 (m, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.36 (m, 2H ), 2.10 (s, 1H), 2.0 (m, 3H), 1.79-1.81 (m, 5H), 1.75-1.74 (m, 3H), 1.69 (m , 2H), 1.55-1.61 (m, 6H), 1.35-1.46 (m, 6H), 0.96 (t, 3H).

Calculated for C43H56BrN3O6 MS (m / z): 790.82, found: 719.32 (M-Br).

(c) Preparation of compound 62-S and compound 62-R

1.10 g of product (b) was dissolved in 10 mL of methanol, separated and purified with a preparation column. Gradient elution was carried out using the mixed acetonitrile and water to collect the eluents of components 62-S and 62-R respectively. The solvent was removed under reduced pressure and the residue was crystallized with isopropanol, obtaining 0.35 g of compound (62-S) and 0.30 g of compound (62-R), respectively.

Example 63

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(4- (3-methyl-1 - {(R ) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethylidene) phenoxy] propyl} -1-azabicyclo [2,2 , 2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(4-acetyl-3-methyl) phenoxy bromide ] propyl} -1 -azabicyclo [2,2,2] octylonium bromide

The above compound was prepared according to the method of Example 57 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(4- (3-methyl-1 - {(R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethylidene) phenoxy] propyl} -1-azabicyclo [ 2,2,2] octylonium

1.27 g (6.0 mmol) of sodium triacetylborohydride was suspended in 50 mL of dichloromethane, 1.12 g (5.0 mmol) of 8-hydroxy-5 - [(R) -2-amino- 1-hydroxyethyl] - (1H) -quinolin-2-one (Preparation 32) and 2.93 g (5.0 mmol) of (a) and 1 drop of acetic acid was added for catalysis. The reaction continued with stirring for 18 hours at room temperature. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, the residue was added with 6 mL of ethanol for freeze lyophilization, and the solid was filtered and collected to obtain 1.86 g of the target product. The yield was 46.8%.

1H NMR (5 ppm) (DMSO-d6) 8.02 (s, 1H), 7.19-7.21 (m, 5H), 6.82 (m, 2H), 6.65-6.60 ( m, 2H), 6.20 (d, 1H), 5.0 (s, 1H), 4.88s, 2H), 4.74 (m, 1H), 4.08 (q, 1H), 3, 94 (m, 3H), 3.68 (d, 1H), 3.15 (m, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.35 (m, 4H ), 2.09 (m, 1H), 2.0 (m, 2H), 1.96 (m, 1H), 1.79-1.81 (m, 5H), 1.75 (m, 1H ), 1.69 (m, 2H), 1.56-1.60 (m, 6H), 1.34-1.46 (m, 9H).

Calculated for C42H56BrN3O7 MS (m / z): 794.81, found: 714.30 (M-Br).

(c) Preparation of compound 63-S and compound 63-R

0.60 g of product (b) was dissolved in 3 mL of methanol, separated and purified with a preparation column. Gradient elution was carried out using the mixed acetonitrile and water to collect components 63-S and 63-R. The solvent was removed under reduced pressure and the residue was crystallized with isopropanol to obtain 0.146 g of compound 63-S and 0.187 g of compound 63-R, respectively.

The following compounds can be synthesized using the starting materials described above and similar methods.

Preparation 33

1,4-Bis (3-bromopropoxy) benzene

110.1 g (1.0 mol) of 1,4-hydroquinone was dissolved in 800 mL of methanol, 606 g (3.0 mol) of 1,3-dibromopropane and 276 g (2.0 mol) of anhydrous potassium carbonate. The reaction mixture was refluxed for 6 hours, and the reaction was stopped. The solid was removed by filtration, and the solvent was removed from the solution to dryness under reduced pressure. 500 mL of ethyl acetate was added for dissolution, and it was washed with water three times (200 mLx3). The organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated to dryness. 209 g of the objective product was obtained in a yield of 59.4%, m / z 351.95.

Preparation 34

2-Methoxy-1,4-bis (3-bromopropoxy) benzene

98.1 g (0.70 mol) of 2-methoxy-1,4-hydroquinone was dissolved in 600 mL of methanol. 404 g (2.0 mol) of 1,3-dibromopropane and 207 g (1.50 mol) of anhydrous potassium carbonate were added. The reaction mixture was refluxed for 8 hours and the reaction was stopped. The solid was removed by filtration. Methanol and excess 1,3-dibromopropane were removed from the solution to dryness under reduced pressure. 400 mL of ethyl acetate was added for dissolution, washed with water three times (200 mLx3). The organic phase was dried over anhydrous magnesium sulfate overnight. The desiccant was filtered off and the filtrate was concentrated to dryness. 189 g of the target product was obtained in a yield of 49.5%, m / z 381.96.

Preparation 35

1.4- Bis (2-bromoethoxy) benzene

The above compound was prepared according to the method of Preparation 32.

Preparation 36

2-methoxy-5-chloro-4- (3-bromopropionamido) benzyl alcohol

(a) Methyl 2-methoxy-5-chloro-4-amino benzoate hydrochloride

500 mL of absolute methanol was placed in a 1000 mL three-necked flask, cooled to approximately -5 ° C in an ice-salt bath. 130 mL of thionyl chloride was added dropwise. After completion of the dropwise addition, 100.5 g (0.50 mol) of 2-methoxy-5-chloro-4-aminobenzoic acid was added with stirring, the solid did not completely dissolve, the reaction mixture was heated naturally up to room temperature, the reaction continued with stirring for 24 hours and the solid was filtered and collected. The solid was dissolved by heating with 250 mL of methanol, frozen for crystallization, filtered to collect the solid, and dried to obtain 94.9 g of the target product in 75.7% yield.

(b) Methyl 2-Methoxy-5-chloro-4- (3-bromopropionamido) benzoate

94.0 g (0.373 mol) of product (a) was dissolved in 300 mL DMF. 37.4 g (0.373 mol) of N-methylmorpholine was added. The reaction mixture was cooled and stirred for 10 minutes in an ice bath. 57.1 g (0.373 mol) of 3-bromopropionic acid and 103 g (0.50 mol) of dicyclohexylcarbodiimide were added. The reaction mixture was warmed to room temperature. After the addition was completed, the reaction continued stirring for 24 hours and the solvent was removed under reduced pressure. The residue was dissolved in 300 mL of ethyl acetate, the solid was filtered off, and the solid was washed with 200 mL of ethyl acetate three times. The ethyl acetate solutions were combined, washed with saturated sodium bicarbonate solution three times (150 mLx3), washed with water three times (150 mLx3) and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated to dryness to obtain 108.3 g of the target product in 82.8% yield, m / z 348.97, 350.97.

(c) 2-Methoxy-5-chloro-4- (3-bromopropionamido) benzyl alcohol

107 g (0.306 mol) of product (b) was dissolved in 400 mL of methanol, cooled in an ice bath. 18.9 g (0.50 mol) of sodium borohydride was added in batches, and the addition was complete in about 1 hour. After the addition was complete, the reaction continued stirring at this temperature for 2 hours. The reaction mixture was gradually warmed to room temperature, and was kept in the reaction for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in 500 mL of dichloromethane, washed 3 times with water (150 mLx3) and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated to dryness to obtain 77.9 g of the target product in a 78.9% yield. m / z 320.98, 322.97.

Preparation 37

2-methoxy-4- (3-bromopropionamido) benzyl alcohol

The above compound was prepared according to the method of Preparation 36.

Preparation 38

3-methyl-4- (3-bromopropionamido) benzyl alcohol

The above compound was prepared according to the method of Preparation 36.

Preparation 39

4- (3-bromopropionamido) benzyl alcohol

The above compound was prepared according to the method of Preparation 36.

Preparation 40

1.1- Dimethoxy-1 - [4- (2-bromoethoxymethyl) phenyl] ethane

(a) 1,1-Dimethoxy-1- (4-methoxyformal) phenylethane

89 g (0.50 mol) of methyl 4-acetylbenzoate was dissolved in 400 mL of methanol. 20 g of hydrogen chloride were introduced. The reaction mixture was heated to 50 ° C and reacted for 4 hours, and the reaction was terminated. Excess methanol and hydrogen chloride gas were removed under reduced pressure. The residue was dissolved in 400 mL of dichloromethane, washed with saturated sodium bicarbonate solution 3 times (150 mLx3), washed 3 times with water (150 mLx3) and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was removed under reduced pressure to obtain 100.80 g of the target product, in a yield of 90.0%, m / z 224.1.

(b) 1,1-Dimethoxy-1- (4-hydroxymethyl) phenylethane

98.0 g (0.437 mol) of product (a) was dissolved in 300 mL of methanol, cooled in an ice bath. 37.6 g (1.0 mol) of sodium borohydride was added in batches, and the addition was complete within 2 hours. After the addition was complete, the reaction mixture was warmed to room temperature, and the reaction continued stirring for 2 hours. Methanol was removed under reduced pressure, the residue was dissolved with 400 mL of dichloromethane, the dichloromethane phase was washed with water three times (150 mLx3), the organic phase was dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was removed under reduced pressure to obtain 68.80 g of the objective product, in a yield of 80.2%, m / z 196.1.

(c) 1,1-Dimethoxy-1 - [4- (2-bromoethoxymethyl) phenyl] ethane

67.0 g (0.341 mol) of product (b) was dissolved in 300 mL of tetrahydrofuran. 15.0 g (0.375 mol) of sodium hydride (60%) was added. The reaction mixture was stirred at room temperature for 15 minutes. 263.2 g (1.40 mol) of 1,2-dibromoethane was added dropwise. The reaction mixture was refluxed for 4 hours. After the addition was complete, the solvent was removed under reduced pressure, the residue was dissolved with 400 mL of dichloromethane and the dichloromethane phase was washed with water three times (150 mLx3). The organic phase was dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was removed under reduced pressure to obtain 88.90 g of the objective product in a yield of 86.0%, m / z 302.0 (MH ).

Preparation 41

1,4-Bis (2-bromoethoxymethyl) benzene

(a) 1,4-Bis (hydroxymethyl) benzene

138.0 g (0.75 mole) of dimethyl terephthalate was dissolved in 400 mL of methanol, cooled in an ice bath. 75.20 g (2.0 mol) of sodium borohydride was added in batches, and the addition was complete in 2 hours. After the addition, the reaction mixture was heated and refluxed for 4 hours. Methanol was removed under reduced pressure, the residue was dissolved with 500 mL of dichloromethane, the dichloromethane phase was washed with water three times (150 mLx3), the organic phase was dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was removed under reduced pressure to obtain 80.80 g of the target product, in a 77.9% yield, m / z 138.07.

(b) 1,4-Bis (2-bromoethoxymethyl) benzene

78.0 g (0.565 mol) of product (a) was dissolved in 500 mL of tetrahydrofuran. 24.86 g (0.622 mol) of sodium hydride was added, stirred at room temperature for 15 minutes. 526.4 g (2.80 mol) of 1,2-dibromoethane was added dropwise. The reaction mixture was refluxed for 8 hours. After the addition was complete, the solvent and excess 1,2-dibromoethane were removed under reduced pressure, and the residue was dissolved in 800 mL of dichloromethane. The dichloromethane phase was washed with water three times (250 mLx3), the organic phase was dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was removed under reduced pressure, obtaining 138.80 g of the objective product with a 69.8% yield, m / z 352.0.

Example 113

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {3- [4- (3 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3-bromopropoxy) phenoxy] propyl bromide } -1 -azabicyclo [2,2,2] octylonium

The above compound was prepared according to Example 3 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - [2-hydroxy-2- (3-formamido-4-benzyloxy) phenyl] ethylbenzylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

1.882 g (5.0 mmol) of (R) -2-benzylamino-1 - [(4-benzyloxy-3-formamido) phenyl] ethanol (Preparation 4) and 3.38 g (5.0 mmol) of (a) To a 50 mL reaction flask, 30 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.5 g (11.0 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 55-60 ° C, and the reaction was carried out at this temperature for 12 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 10 mL of isopropanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 3.26 g of the target product. The yield was 67.7%. Calculated for C55H68BrN3557 MS (m / z): 963.0, found: 883.4 (M-Br).

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium

3.10 g (3.22 mmol) of the product (b) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.6 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.4-0.43 MPa and the temperature was room temperature. After 20 hours of reaction, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol. 1.38 g of the objective solid compound was obtained in a yield of 54.7%.

1H NMR (5 ppm) (DMSO-ds) 8.21 (s, 1H), 7.40 (m, 1H), 7.18-7.23 (m, 5H), 6.66-6.71 ( m, 2H), 5.0 (s, 1H), 4.74 (m, 1H), 4.0 (s, 1H), 3.92 (s, 2H), 3.68 (d, 2H) , 3.15 (m, 1H), 2.91 (m, 1H), 2.83 (m, 1H), 2.54 (m, 2H), 2.42 (S, 1H), 2.35 ( m, 2H), 2.10 (s, 1H), 2.0 (m, 3H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.69 ( m, 2H), 1.55-1.61 (m, 8H), 1.34-1.46 (m, 6H); calculated for the M (m / z) of C41H56BrN3O7: 782.8, found: 702.3 (M-Br).

Example 114

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {2- [4- (2 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyoxyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octiIonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2-bromoethioxyl) phenoxy] ethyl bromide } -1 -azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 1 (a)

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {2- [4- (2 - {(R) - [2- (3-benzyloxymethyl-4-benzyloxy) phenyl-2-hydroxy] ethylbenzylamino} ethioxy) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

2.40 g (5.28 mmol) of (R) -1 - [(4-benzyloxy-3-benzyloxymethyl) phenyl] -2-benzylaminoethanol (Preparation 1) and 3.38 g (5.28 mmol) were added From (a) to a 50 mL reaction flask, 20 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.475 g (10.60 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 65-70 ° C, and the reaction was carried out held at this temperature for 8 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, the residue was dissolved in isopropanol and frozen for crystallization, and the solid was filtered and collected to obtain 3.42 g of the target product. The yield was 64.0%. Calculated for C6üH71BrN2O7 MS (m / z): 1012.1, found: 932.4 (M-Br).

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyoxyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium

3.30 g (3.26 mmol) of product (b) was placed in a hydrogenation reaction kettle, 20 mL of methanol was added for the solution, 0.8 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 10 hours of reaction, the reaction was stopped. The catalyst was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved with isopropanol and frozen for crystallization. 1.38 g of the objective solid compound was obtained in a yield of 57.1%. 1H NMR (5 ppm) (DMSO-d6) 7.19-7.22 (m, 5H), 6.95-7.01 (m, 2H), 6.66 (d, 2H), 6.63- 6.59 (m, 3H), 5.0 (s, 1H), 4.79 (s, 2H), 4.74 (m, 1H), 4.04 (t, 2H), 4.06 ( t, 2H), 3.93 (d, 1H), 3.68 (d, 1H), 3.15 (m, 1H), 2.97 (t, 2H), 2.90 (m, 1H), 2.74 (m, 1H), 2.78 (t, 2H), 2.21 (S, 1H), 2.10 (s, 1H), 2.0 (m, 3H), 1.79-1 , 81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.56-1.60 (m, 6H), 1.34-1.46 (m, 6H ); Calcd for C3gH53BrN2O7 MS (m / z): 741.8, Found: 661.3 (M-Br).

Example 115

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {3- [5-chloro-2-methoxy-4 - ({(( R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl)] ethoxy-1 - {3 - [(5-chloro-2-methoxy- 4-hydroxymethyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [5-chloro-2-methoxy-4- methanesulonyloxymethyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (b).

(c) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [5-chloro-2-methoxy-4- ({(R) - [2-hydroxy-2- (8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylbenzylamino} methyl) anilino] oxopropyl) -1-azabicyclo [2,2, 2] octylonium

2.0 g (5.0 mmol) of 8-benzyloxy-5 - [(R) -2-benzylamino-1-hydroxyethyl] - (1 H) -quinolin-2-one (Preparation 2) and 4 were added, 28 g (5.0 mmol) of (b) to a 50 mL reaction flask, 30 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.475 g (10.57 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 65-70 ° C. The reaction was carried out at this temperature for 5 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure. The residue was dissolved in 10 mL of ethanol, frozen and crystallized. The solid was filtered and dried to obtain 2.96 g of the target product. The yield was 51.2%. Calculated for MS (m / z) of C64H70BrClN4O9: 1154.49, found: 1073.86 (M-Br).

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {3- [5-chloro-2-methoxy-4- ({(R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2, 2] octylonium

2.88 g (2.49 mmol) of product (c) was placed in a hydrogenation reaction kettle, 20 mL of methanol was added for the solution, 0.7 g of 10% Pd-C was added, introduced hydrogen, the pressure was kept at 0.43 MPa and the temperature was at room temperature. After 18 hours of reaction, hydrogen uptake was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved and crystallized with ethanol. 1.48 g of the objective solid compound was obtained in a yield of 70.7%.

1H NMR (5 ppm) (DMSO-ds) 8.10 (s, 1H), 8.01 (s, 1H), 7.36 (d, 1H), 7.18-7.21 (m, 5H) , 6.97 (d, 1H), 6.94 (d, 1H), 6.71 (d, 1H), 6.52 (d, 1H), 5.0 (s, 1H), 4, 74 (m, 1H), 3.93 (m, 1H), 3.81 (d, 2H), 3.73 (s, 3H), 3.68 (d, 1H), 3.15 (m, 1H ), 2.90 (m, 1H), 2.84 (m, 1H), 2.74 (t, 2H), 2.33 (t, 2H), 2.05 (s, 1H), 2, 0 (m, 4H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.68 (m, 2H), 1.56-1.60 (m, 6H), 1.35-1.46 (m, 6H).

Calculated for MS (m / z) of C42H52BrClN4O7: 840.24, found: 759.77 (M-Br).

Example 116

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4 - ({(R) - [2-hydroxy- 2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octilonium

(a) (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl] ethoxy-1 - [3- (4-hydroxymethylanilino) oxopropyl] -1-azabicyclo bromide [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (a).

(b) (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl] ethoxy-1- [3- (4-methylsulfonyloxymethylanilino) oxopropyl] -1 -azabicyclo bromide [2,2,2] octylonium

The above compound was prepared according to the method of Example 57 (b).

(c) Bromide of (R) - (-) - 3 - [(R) -2-benzyloxyformal-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4 - ({(R) - [2 -hydroxy-2- (6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylbenzylamino} methyl) anilinoformyl] ethyl} -1-azabicyclo [2,2,2] octylonium

2.02 g (5.0 mmol) of 8 - [(R) -1-hydroxy-2-benzylamine] ethyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one (Preparation 5) and 3.96 g (5.0 mmol) to a 50 mL reaction flask, 30 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.0 g (7.35 mmol) of anhydrous potassium carbonate was added, the temperature of the reaction mixture increased to 65-70 ° C. The reaction was carried out at this temperature for 10 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, the residue was added with 10 mL of isopropyl alcohol for freeze lyophilization, and the solid was filtered and collected to obtain 2.88 g of the target product. The yield was 60.0%.

Calculated for C62H69BrN4Og MS (m / z): 1094.0, found: 1014.38 (M-Br).

(d) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4 - ({(R) - [2 -hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium

2.70 g (2.47 mmol) of the product (c) was placed in a hydrogenation reaction kettle, 20 mL of methanol was added for the solution, 0.6 g of 10% Pd-C was added, hydrogen was introduced and the pressure was kept at 0.43 MPa. After carrying out the reaction at room temperature for 16 hours, the absorption of hydrogen was stopped and the reaction was stopped. The catalyst was removed by filtration, the filtrate was concentrated to dryness, and the residue was crystallized from isopropanol. 1.26 g of the objective solid compound was obtained in a yield of 65.4%.

1H NMR (5 ppm) (DMSO-ds) 8.05 (s, 1H), 8.0 (s, 1H), 7.52 (d, 2H), 7.19-7.21 (m, 5H) , 7.04 (d, 2H), 6.65 (d, 1H), 6.20 (d, 1H), 5.0 (s, 1H), 4.88 (s, 2H), 4.74 ( m, 1H), 3.93 (d, 1H), 3.81 (d, 2H), 3.68 (d, 1H), 3.15 (m, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.74 (t, 2H), 2.33 (t, 2H), 2.10 (m, 2H), 2.0 (m, 2H), 1.96 ( m, 1H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.56-1.60 (m, 6H), 1 , 34-1.46 (m, 6H).

Calculated for C4üH51BrN4O7 MS (m / z): 779.76, found: 700.33 (M-Br).

Example 117

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {2- [4- (2 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethylidene) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium

(a) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1- {2- [4- (1,1-dimethoxyethyl) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 1 (a).

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethylidene) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium

0.981 g (5.0 mmol) of (R) -2-amino-1 - [(4-hydroxy-3-formamido) phenyl] ethanol (Preparation 30) and 3.09 g (5.0 mmol) of (a) To a 250 mL reaction flask, 50 mL of dichloromethane was added. After the reaction mixture was stirred for 10 minutes, 2.54 g (12.0 mmol) of sodium triacetylborohydride was added, and 1 drop of acetic acid was added for catalysis. The reaction mixture reacted for 24 hours at room temperature, and thin-layer detection showed that the reaction was complete. The reaction was stopped, and the reaction mixture was filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, 5 mL of ethanol was added to the residue for freeze lyophilization, and the solid was filtered and collected to obtain 1.62 g of the target product. The yield was 43.0%. 1H NMR (5 ppm) (DMSO-d6) 8.21 (s, 1H), 7.40 (m, 1H), 7.18-7.20 (m, 5H), 7.14 (d, 2H) 7.05 (d, 2H), 6.76 (dd, 1H), 6.64 (dd, 1H), 5.0 (s, 1H), 4.74 (m, 1H), 4.63 (s, 2H), 4.08 (m, 1H), 4.0 (s, 1H), 3.93 (d, 1H), 3.68 (d, 1H), 3.47 (t, 2H), 3.15 (m, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.53 (t, 2H), 2.10 (s, 1H), 1, 96-2.0 (m, 3H), 1.79 1.81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.55-1.61 (m , 6H), 1.34-1.46 (m, 6H), 1.38 (d, 3H); calculated for C4üH54BrN3O6 MS (m / z): 752.78, found: 672.32 (M-Br).

(c) Resolution of the 117-S isomer and the 117-R isomer

0.80 g of product (b) was dissolved in methanol, separated with a preparation column, gradient elution was carried out with methanol and water, the component peaks of the S isomer and R isomer were collected, respectively, drained under reduced pressure, the residue was recrystallized with ethanol obtaining 0.24 g of the S isomer and 0.28 g of the R isomer.

Example 118

(R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - [2- hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxymethyl) benzyloxy] ethyl} -1 -azabicyclo [2,2,2] octylonium

(a) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2-bromoethoxymethyl) benzyloxy] ethyl bromide } -1 -azabicyclo [2,2,2] octylonium

The above compound was prepared according to the method of Example 1 (a).

In a 250 mL three-necked flask, 35 mL of absolute ethanol was added, 5.0 g (15.85 mmol) of (R) - (-) - 3 - [(R) -2-hydroxy- 2-cyclopentyl-2-phenyl] ethoxy-1-azabicyclo [2,2,2] octane (Preparation 2). After the reaction mixture was stirred to dissolve, 44.66 g (126.3 mmol) of 1,4-bis (2-bromoethoxymethyl) benzene (Preparation 40) was added. The reaction was carried out with stirring at room temperature for 18 hours. Ethanol was removed under reduced pressure and the residue was subjected to column chromatography to obtain 8.50 g of the objective product in a yield of 80.4%. MS (m / z) 686.18, 688.17.

(b) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - 2-hydroxy-2- (5-benzyloxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylbenzylamino} ethoxymethyl) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octilonium

2.02 g (5.0 mmol) of 8 - [(1R) -1-hydroxy-2-benzylamine] ethyl-6-benzyloxy-2H-1,4-benzoxazin-3 (4H) -one (Preparation 5) and 3.38 g (5.0 mmol) from (a) to a 50 mL reaction flask, 30 mL of dioxane was added. After the reaction mixture was stirred for 10 minutes, 1.0 g (7.35 mmol) of anhydrous potassium carbonate was added and the temperature of the reaction mixture increased to 75-80 ° C. The reaction was carried out at this temperature for 12 hours. Thin layer detection showed the reaction to be complete. The reaction was stopped, and the reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The solvent was removed from the filtrate under reduced pressure, the residue was added with 15 mL of ethanol for freeze lyophilization, and the solid was filtered and collected to obtain 3.36 g of the target product. The yield was 67.8%. MS (m / z) 901.45.

(c) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxymethyl) benzyloxy] ethyl} -1-azabicyclo [2,2,2 ] octilonium

3.20 g (3.23 mmol) of product (b) was placed in a hydrogenation reaction kettle, 30 mL of methanol was added for the solution, 0.6 g of 10% Pd-C was added, hydrogen was introduced, the pressure was kept at 0.43 MPa and the temperature was room temperature. After 18 hours of reaction, hydrogen absorption was stopped, the reaction was stopped, the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was crystallized from ethanol. 1.48 g of the objective solid compound was obtained in a yield of 56.5%. 1H NMR (5 ppm) (DMSO-ds) 8.0 (s, 1H), 7.15-7.20 (m, 5H), 7.12 (d, 4H), 6.65 (d, 1H) , 6.20 (d, 1H), 5.0 (s, 1H), 4.88 (s, 2H), 4.73 (m, 1H), 4.63 (s, 4H), 3.93 (d, 1H), 3.68 (d, 1H), 3.49 (t, 2H0.3.47 (t, 2H), 3.15 (m, 1H), 2. 91 (m, 1H), 2.84 (m, 1H), 2.72 (t, 2H), 2.53 (t, 2H), 2.10 (s, 1H), 2.0 (m, 2H), 1.96 (m , 1H), 1.79-1.81 (m, 3H), 1.75 (m, 1H), 1.69 (m, 2H), 1.55-1.61 (m, 6H), 1, 34-1.46 (m, 6H) Calculated for Em (m / z) of C42H56BrN3Os: 810.8, found: 730.3 (M-Br).

The following compounds can be prepared using the starting materials synthesized above and synthesis methods:

Experimental Example 1: Intensity of the response of guinea pig tracheal smooth muscle constriction induced by antagonization of carbachol (CC) according to the compounds of the invention

Isolated tracheal smooth muscle guinea pig specimen preparation: After a guinea pig was anesthetized by urethane, the trachea was rapidly removed between the larynx and carina and placed in Krebs-Henseleit (KH) solution (composition (g / L ): NaCl 6.92, KCl 0.35, CaCl ² 0.28, KH ² PO ⁴ 0.16, MgSO4 ⁷ H ² O 0.4568, NaHCO32.1, glucose 2.0) with gas mixture of 5 % CO ² and 95% O ² added. After loose connective tissue and fat around the trachea were separated, the trachea was isolated to be a sheet of trachea with a width of approximately 3 mm and a length of 20 mm and with two ligated ends, and arranged in a constant temperature bath of 37 ° C (pH 7.4) containing 5 mL of KH solution, with the gas mixture containing 5% CO ² and 95% O ² continuously added. The upper end was connected with a muscle tension transducer and the specimen was administered at a resting tension of 1.0 g. Changes in muscle tension were recorded, the nutrient solution was changed every 20 min and the experiment started after 60 min of equilibrium.

Administration method: After stabilizing the trachea sheet, 3x10-6 mol / L of CC was added to the bath. When the constriction tension of the tracheal sheet reached a peak level, the example compounds, ipratropium bromide and tiotropium bromide, were added in a Magnus bath for a cumulative dosage regimen with a dose of 10-9 ~ 10-5. moles, respectively. The diastolic condition of the tracheal lamina was observed. If no response occurred (below the threshold concentration), the next dose was added in order. If any response occurred, the next dose was added until its diastolic platform was reached. The above operation was repeated until the shrinkage curve reached the minimum. Finally, 10-6 mol / L isoproterenol was added to establish maximum relaxation, and the curve was recorded.

Statistical methods: Statistics were performed using the Sigma Stat statistical software package, the data was analyzed using analysis of variance. The Student-Newman-Keuls (SNK) test was used in comparison between multiple average numbers of samples. The statistical test level was a = 0.05 (two-tailed). EC ⁵⁰ (95% confidence index) was calculated by Shanghai Science and Technology Press POMS version 2.0 software.

3 x 10-6 mol / L CC can cause guinea pig tracheal smooth muscle to produce a sustained and stable constriction response. In the cumulative regimen, the test compounds and the ipratropium bromide and tiotropium bromide control drugs were added to the Magnus bath, and each of the example compounds and each of the control drugs were able to relax CC-induced constriction of tracheal smooth muscle. The results are shown in Table 1.

Table 1: The EC ⁵⁰ (| uM) of guinea pig tracheal smooth muscle constriction induced by some compounds of the invention that antagonize CC with a concentration of 3 x 10-6 mol / L in vitro

The results in Table 1 show that all the compounds designed by the invention have the effect of blocking carbachol-induced constriction of guinea pig tracheal smooth muscle, a considerable number of compounds have stronger blocking effect than the positive control agent bromide. of ipratropium, and some compounds have intensity of action comparable to that of the positive control agent tiotropium bromide. The appearance time of the compound of the invention and ipratropium bromide are shorter than that of tiotropium bromide, on the contrary, the appearance time of tiotropium bromide is low. The compounds of the present invention and tiotropium bromide have a long duration of action, but ipratropium bromide has a short duration of action.

Experimental Example 2: Determination of the antagonist intensity and duration of action of the bronchoconstriction response in guinea pig trachea induced by the compound of the invention that antagonizes methacholine (Mc)

Determination of tidal volume, airway flow rate and transpulmonary pressure: 1.5 g / kg of urethane was injected intraperitoneally to anesthetize the guinea pig. The guinea pig was fixed supine, subjected to tracheal intubation and inserted with a permanent needle while the external jugular vein was separated. The guinea pig was enclosed in a body plethysmograph, a blunt needle for intubation was inserted into the thoracic cavity between the 4 ~ 5 ribs of the guinea pig prothorax, and the intrathoracic pressure could be measured (with a negative value of a column of water). of a water manometer and a fluctuation with the guinea pig's respiration as markings). After stabilization, guinea pig tidal volume, airway flow rate, and transpulmonary pressure values prior to Mc administration were recorded by a MedLab biological signal collection and processing system as baseline values. 10 pg / kg body weight of Mc was injected intravenously. Changes in guinea pig airway flow, tidal volume and transpulmonary pressure were observed within 5 minutes. Calculation of Rvr and Ddin: the changes of the percentage increase of the Rvr value and the decrease of the percentage of Ddin after the inhalation of Mc were calculated.

The calculation formulas for Rvr and Cdin were respectively:

Dose-effect relationship: For each of the compounds of the Example, 27 guinea pigs were randomly divided into three groups: a group of 0.1 pg / kg of the compounds [48, 70, 99, 138] of the invention, a group of 0.3 pg / kg of the compounds [48, 70, 99, 138] of the invention and a group of 1 pg / kg of group of the compounds [48, 70, 99, 138] of the invention, and there was 15 guinea pigs from a vehicle control group. Pulmonary airway resistance (Rvr) and dynamic compliance (Ddin) were measured 5 min after airway dripping with the above drug concentration for 30 min, and intravenous injection of 10 pg / kg body weight of Mc for excitement.

Time-effect relationship: After the guinea pigs were anesthetized, 0.5 pg / kg and 1 pg / kg of the compounds [48, 70, 99, 138] of the invention were dripped into the airways. Separately, 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h, and 24 h after administration, 10 pg / kg Mc was injected intravenously. body weight for arousal, and respiratory tract resistance ( R ^vr ) and pulmonary dynamic compliance ( D ^din ) were measured in 5 min.

Dose-effect relationship: The administration doses of the compounds [48, 70, 99, and 138] of the invention were 0.1 pg / kg, 0.3 pg / kg and 1 pg / kg, respectively. 30 min after airway drip, Mc of 10 pg / kg body weight was injected intravenously for arousal, and pulmonary airway resistance ( R ^vr ) and dynamic compliance ( D ^din ) were measured. in 5 min. The results are shown in Table 2 below:

Table 2. Bronchial contraction response in guinea pigs induced by the compounds of Example 48, 70, 99, 138 of the invention that antagonize the effect-dose relationship of Mc (mean ± SEM)

Statistical methods: one-sided ANOVA. The comparison between groups was tested by the Bonferroni method. Comparison with the vehicle control group was * P <0.05, ** P <0.01, *** P <0.001.

After intravenous injection of Mc 10 pg / kg, guinea pig airway resistance increased by 320%, dynamic lung compliance decreased by 71%. 0.1 pg / kg, 0.3 pg / kg, and 1 pg / kg of compounds [48, 70, 99, 138] were dripped into the guinea pig's airways, respectively, which inhibited the increase in resistance of airways and decreased dynamic lung compliance in a dose-dependent manner. The inhibitory rates of compound 48 on the increase in airway resistance in the three dose groups were 66.2% (p <0.01), 88.3% (p <0.001), and 91.6% ( p <0.001), respectively. The inhibitory rates for the reduction of dynamic lung compliance were 32.2% (p> 0.05), 48.9% (p <0.001), and 50.1% (p <0.001), respectively. The inhibitory rates of compound 70 on the increase in airway resistance in the three dose groups were 69.6% (p <0.01), 86.5% (p <0.001), and 92.1% ( p <0.001), respectively. The inhibitory rates for the reduction of dynamic lung compliance were 34.2% (p> 0.05), 47.8% (p <0.001), and 49.3% (p <0.001), respectively. The inhibitory rates of compound 99 on the increase in airway resistance in the three dose groups were 73.5% (p <0.01), 86.8% (p <0.001), and 91.9% ( p <0.001), respectively. The inhibitory rates of dynamic lung compliance were 35.0% (p> 0.05), 48.8% (p <0.001), and 49.7% (p <0.001), respectively. The inhibitory rates of compound 138 on the increase in airway resistance in the three dose groups were 74.8% (p <0.01), 88.9% (p <0.001) and 92.6% (p <0.001), respectively. The inhibitory rates of dynamic lung compliance were 31.0% (p> 0.05), 48.2% (p <0.001), and 49.9% (p <0.001), respectively.

Time-effect relationship: After intravenous injection of Mc 10 pg / kg, the airway resistance of guinea pigs increased by 328%. After 1 pg / kg of compounds [48, 70, 99, 138] was dripped into the airways of guinea pigs for 0.25 h, the inhibitory rate on the increase in airway resistance was 80% or more. The maximum inhibitory rate can reach 90% or more after 1 hour. With time extension, the inhibitory rate of airway resistance increase after 24 hours was still 85% or more, and there were statistical differences compared to the vehicle control group (p <0.01 ~ 0.001 ). To confirm the precision of the results, the administration dose of the compounds [48, 70, 99, 138] was reduced to 0.5 pg / kg. The results showed that after 0.5 pg / kg of compounds [48, 70, 99, 138] was dripped into the airways of guinea pigs for 12 h, the inhibitory rate in airway resistance was 85%. or more (p <0.001), after 24 h, the inhibitory rate in airway resistance was 75% or more (p <0.01). There was no significant difference in the inhibitory rate in airway resistance between 1 pg / kg of the compounds [48, 70, 99, 138] and 0.5 pg / kg of the same after 12 hours. However, after 24 h, there was no significant difference in the inhibitory rate of airway resistance between 1 pg / kg of compounds [48, 70, 99, 138] and 0.5 pg / kg of compounds. (p <0.05). The above results suggested that 1 pg / kg of compounds [48, 70, 99, 138] and 0.5 pg / kg thereof were long-acting tracheal dilators, of which the time of action after administration of the airway drip was greater than 24 hours.

Experimental example 3: Study on the activity and selectivity of the compounds of the invention for ^{recombinant human p 1} and p ² adrenoceptors expressed in HEK and CHO cells

To measure the activity and selectivity of agonists for human p ¹ and p ² adrenoceptors, the accumulation of expressed receptors cAMP was measured in each recombinant cell line. CAMP was determined by radioimmunoassay for homology, that is, cells were washed with PSB buffer solution and suspended in the buffer solution at room temperature to grow up to 30000-40000 cells per well. The test compound was diluted with PSB buffer solution containing 0.1% BSA and tested at 11 gradient concentrations ranging from 100 uM to 0.1 pM. For p ¹ adrenoceptor analysis, 10 nM ICI118551 was added to block expression of p ² adrenoceptors in HEK293 cells. After adding the compound to the suspended cells, the scintillation plate was incubated at 37 ° C for 10 minutes, the reaction was terminated with ice cold detection buffer solution, and its radioactivity was measured after storage at 4 ° C. overnight.

Agonist activity (pCEsü value) was analyzed by regression using the S-type dose response model from the software package (GraphPad Software, San Diego, CA). Selectivity was calculated from the ratio of measured cAMP of p ¹ and p ² adrenoceptors, which was expressed as sel. P ¹ / P ² = (EC ⁵⁰ (p ¹ ) / ECs ⁰ (P ² )).

Table 3. Results of the study on the activity and selectivity of some compounds of the invention for pi and p ^{2 adrenoceptors}

Result of the analysis: The compounds of the invention have good agonist activity and functional selectivity for the p ² adrenoceptor.

Experimental Example 4: Study on the determination of the in vitro activity and selectivity of the compounds of the invention for the ^{recombinant human M 1} , M ² , M ³ receptor subtypes expressed in CHO cells

Transfected CHOmp, CHOm ² and CHOm3 cells were grown in DMEM medium (containing 15% fetal bovine serum, 4 mM L-glutamine, 1% non-essential amino acid and 1% antibiotic / antifungal) in incubation oven at 37 ° C and 5% CO ² , respectively.

With reference to the bibliography [Hu Ya'er, Shi Ju, Xia Zongqin; Some pharmacological and biological properties of CHOm2 cells transfected with M2 receptor cDNA [J]. Nuclear Science and Technology, 1999, 11 (22): 642-646], when cells grew in the culture flask and proliferated to form monolayer cells, and the bottom of the flask was covered by approximately 90% (approximately 48 h after inoculation), the medium was discarded, and washed twice with PBS buffer solution (pH 7.4). The cells were then scraped with a glacial phosphate buffer solution (pH 7.7, containing 5 mmol / L MgCL). The collected cells were homogenized with a Teflon-glass homogenizer, the homogenate was centrifuged at 20000r x 20 min at low temperature, and the precipitate was homogenized with a reaction buffer solution to form a membrane protein suspension. The amount of protein added to each of the reaction tubes was: m1 (approximately 0.05 mg), m2 (0.05 mg), m3 (0.1 mg), respectively, the concentration of [3H] -QNB it was 0.1-2.16 nmol / L. 1 pmol / L atropine was added in non-specific binding tube. The total reaction volume was 300 pL. The resulting solution was then reacted at 25 ° C for 5 h and quenched with a glacial reaction buffer solution, and collected on a glass fiber membrane using a multi-head cell harvester. After drying at 80 ° C, the filter membrane sheet was placed in a liquid scintillation vial, followed by the addition of 5 mL of liquid scintillation agent and then kept in a dark place overnight, with cpm measured. by a liquid scintillation spectrometer. The Bmax and Kd values were calculated by the Graphpad prism software.

3H-QNB, which is non-selective for the M receptor, was added to each experimental tube as a labeling ligand, and the final concentration of each tube was m1, m3 (1.042 nmol / L), m2 (1.81 nmol / L ). At the same time, different concentrations of tiotropium bromide, ipratropium bromide and each test compound were added, the final concentration was 10-10 ~ 10-4 mol / L, amounting to 11 doses. The same amount of membrane protein sample was added (same as the saturation experiment mentioned above). The total volume of the reaction was 300 pL, and the competitive binding reaction was carried out. Another non-specific binding tube was established to measure non-specific binding with a large amount of atropine (final concentration of 1 pmol / L). After the reaction was carried out at 25 ° C for 5 hours and terminated with ice cold reaction buffer solution, the reaction product was collected on a glass fiber filter membrane using a multi-cell harvester. heads. After drying at 80 ° C, the filter membrane was placed in a liquid scintillation vial, 5 mL of liquid scintillation agent was added and kept in a dark place overnight. Cpm was measured with a liquid scintillation meter. Ki values of each compound were calculated up to M receptor subtypes by Graphpad prism software. The selectivity of the M receptor subtype was compared between tiotropium bromide, ipratropium bromide, and each test compound.

Table 4 Experimental results of determination of the activity and selectivity of some compounds of the invention by the M receptor agonist

The experimental results show that the compounds of the invention have the highest selectivity for the M ³ receptor, followed by the M ¹ receptor and the lowest selectivity for the M ² receptor, and the compounds have a strong effect on the M ³ and M receptors. ¹ . Compared with the state of the art, the invention has obvious advantages in the treatment of rhinitis, airway hypersensitivity, chronic bronchitis, COPD and other diseases.

Experimental example 5: Activity in MABA, M receptor and p ² adrenoreceptor determined in isolated guinea pig trachea

(1) The effect of guinea pig tracheal smooth muscle constriction induced by the example compounds that antagonize carbachol (CC)

Preparation of a specimen of tracheal smooth muscle isolated from a guinea pig: same as Experimental Example 1.

Administration method: After the trachea sheets stabilized, carbachol was added with a final concentration of 3x10.6 mol / L, and the administration started when the pressure value of the trachea sheets increased to a stable platform. The experiments were divided into blank group and each sample from the test administration group. The DMSO solution prepared from the K-H solution and 50 µl of each test sample solution were added to each group, respectively. The test sample administration group was added with 10-9, 0.3x10-8, 10-8, 0.3x10-7, 10-7, 0.3x10-6 and 10-6 mol / L of compound of test and control substance in cumulative concentration. The blank group was added with corresponding dilute DMSO solution. Medlab was used to record the degree of smooth muscle relaxation of the tracheal sheets. Finally, isoproterenol with a final concentration of 10-5 mol / L was added as 100% relaxation. The results are shown in Table 5.

(2) Blocking effect of the example compounds on guinea pig tracheal smooth muscle receptor M

Preparation of a specimen of tracheal smooth muscle isolated from a guinea pig: same as Example 1 of the experiment.

Administration method: After the trachea sheets stabilized, propranolol hydrochloride solution with a final concentration of 10-5 mol / L was added to block the p receptor for 10 min, carbachol was added with a final concentration of 3x10-6 mol / L (observing compound M receptor antagonism after propranolol blocked the p receptor) and administration started when the pressure value of the tracheal sheets increased to a stable platform. The experiments were divided into a blank group, a propranolol + blank group, administration group of each test sample, and a propranolol + administration group of each test sample. DMSO solution prepared by KH solution and 50 µl of test sample solution were added to each group of the blank group and administration group of each test sample, respectively. To the propranolol + blank group and propranolol + group administration of each test sample was added 50 μl of propranolol solution for 10 min, respectively, and then DMSO solution prepared from KH solution and 50 μl of solution were added of test sample. Compounds to be tested with final concentrations of 10-9, 0.3x10-8, 10-8, 0.3x10-7, 10-7, 0.3x10-6 and 10- were added to the test sample administration group. 6 mol / L cumulative concentration, and corresponding dilute DMSO solution was added to the blank group. Propranolol + administration of each test sample was added to the propranolol group for 10 min, and then the compounds to be tested were added with final concentrations of 10-9, 0.3x10-8, 10-8, 0.3x10-7, 10-7, 0.3x10-6 and 10-6 mol / L in accumulated concentration. After adding propranolol + blank propranolol group for 10 min, corresponding dilute DMSO solution was added. Medlab was used to record the degree of relaxation of tracheal smooth muscle, finally sodium nitroprusside was added with a final concentration of 2x10-4 mol / L as 100% relaxation. The results are shown in Table 5.

(3) Antagonism of the example compounds on the p ² receptor in guinea pig tracheal smooth muscle

Preparation of a specimen of tracheal smooth muscle isolated from a guinea pig: same as Experimental Example 1.

Administration method: After the trachea sheets stabilized, histamine solution with a final concentration of 3x10-5 mol / L was added over 10 min, carbachol was added with a final concentration of 3x10'6 mol / L (observing antagonism of p) receptors and administration started when the pressure value of the tracheal sheets increased to a stable platform. The experiments were divided into a blank group, a histamine + blank group, administration group of each test sample, and a histamine + administration group of each test sample. DMSO solution prepared by K-H dissolution and 50 gl of sample solution sample were added to each group of the blank group and administration group of each test sample, respectively. To the histamine + target group and to the histamine + group, administration of each test sample was added 50 gl of histamine solution for 10 min, respectively, then DMSO solution prepared by KH solution and 50 gl of sample solution were added. test. Compounds to be tested with final concentrations of 10-9, 0.3x10-8, 10-8, 0.3x10-7, 10-7, 0.3x10-6 and 10- were added to the test sample administration group. 6 mol / L in cumulative concentration, and the corresponding dilute DMSO solution was added to the blank group. Histamine + administration of each test sample was added to the histamine + administration group for 10 min, and then final concentrations of 10-9, 0.3x10-8, 10-8, 0.3x10-8 were added to the test compounds , 10-7, 0.3x10-6 and 10-6 mol / L in accumulated concentration. After histamine was added to the histamine + blank group for 10 min, corresponding dilute DMSO solution was added. Medlab was used to record the degree of smooth muscle relaxation of the tracheal sheets. Finally theophylline was added with a final concentration of 2x10-4 mol / L as 100% relaxation. The results are shown in Table 5.

Table 5. Results of the experiment of pharmacodynamic activity of some compounds of the invention in previously constricted isolated tracheal M (MA) receptor agonists, p ² (BA) and bifunctional receptor agonists (MABA)

The results show that the compounds of the invention have simultaneously strong M receptor blocking function and p receptor agonist function, and these two functions of a large number of compounds have a degree of MA: BA correspondence that reaches substantially 1 -1 , 5: 1. The degree of correspondence of the compound of Example 113 almost reaches 1: 1.

Experimental Example 6: Acute toxicity test of the compounds of the invention in Beagle dogs by simple nasogastric tube

Test compounds:

Example compounds 7, 12, 61,69, 80, 82, 94, 113, 122 and 131 of the invention

Control compounds:

(1) The compound of Example 1 in WO2010126025: 4 - ({[5- (2 - {[4 - ({[(2R) -2-hydroxy-2- (8-hydroxy-2-oxo -1,2-dihydroquinolin-5-yl) ethyl] amin o} methyl) phenyl] carbamoyl} ethyl) -2-phenylphenyl] carbamoyl} oxy) -1,1-dimethylpiperidin-1-onium (prepared according to the method of bibliography).

(2) The compound of Example 1 in WO2010004517: 5 - [(1R) -2 - ({9- [4 - ({3 - [(R) -cyclohexyl (hydroxy) benzyl) -1 H-1, 2,4-triazol-1 -yl} methyl) piperidin-1-yl] nonyl} amino) -1-hydroxyethyl] -8-hydroxyquinolin-2 (1H) -one (prepared according to the literature method).

Testing method:

Beagle dogs were randomly divided into two groups, half male and half female, and injected intravenously (iv) with 7.5% ethanol solution of the compounds of the invention and the control compound. Each compound was put into two dosage groups of 0.01 mg / kg and 0.10 mg / kg. Changes in heart rate were observed after administration (30 min - 4 h after administration), and the results were shown in Table 6.

Table 6 Changes in heart rate after iv administration of the compounds of the invention in Beagle dogs

As can be seen from Table 6, the heart rate of Beagle dogs does not change significantly after iv administration of the compounds of the present invention at the dose of 0.1 mg / kg, while the control compound increases significantly. the heart rate of Beagle dogs at the dose of 0.01 mg / kg. Thus, the compounds of the invention have less toxicity and side effects.

Experimental example 7: Stability tests of the compounds of the invention in liver microsomes and lung homogenates in vitro,

1. Test compound in liver microsome test:

Example compounds 7, 12, 61,69, 80, 82, 94, 113, 122 and 131 of the invention

Control compound:

(1) Compound of Example 1 in patent document WO2010126025, (2) compound of Example 1 in patent document WO2010004517.

Experimental method: The example compounds of the invention and the control compound were incubated respectively with the hepatic microsomes of SD rats and Beagle dogs at 37 ° C for 0, 2, 5, 10, 15, 20, 30 min, and the samples were respectively analyzed by LC-MS / MS when the reaction ended. The area ratio of the sample at 0 min was considered as 100%, and the remaining percentage of the compound after incubation was obtained at different times at each time comparing with the sample. With the natural logarithm of this percentage on the ordinate and time on the abscissa, a scatter diagram was drawn to simulate a straight line with a negative slope of k. The parameters were calculated according to the formula.

t ^1/2 (min) = 0.693 / k

0.693 x Liver weight (g / kg) x P450 (m g / g)

ELint (m L / m in / kg)

0.5 (m g / m L) x t 1/2 (min)

Liver weight indicates the weight of the liver (g) per kilogram of body weight, and P450 indicates the amount (mg) of the enzyme P450 per gram of liver.

The values of the different species are shown in the table below:

ELint (mL / min / kg) x Qh (mL / min / kg)

ELhep (mL / nnn / kg) - EL.nt (mL / min / kg) Qh (mL / min / kg)

Qh represents the hepatic blood circulation, and the values of different species are shown in the table above.

The hepatic extraction rate (ERh) was calculated according to ERh = Clhep / Qh, and the results are shown in Table 7.

Table 7 Conditions of metabolic stability of the compound in liver microsomes in vitro

As shown in Table 7, the compounds of the invention have poor metabolic stability in SD rat and Beagle dog liver microsomes, metabolized more rapidly and are difficult to accumulate in vivo, while the control compound has better metabolic stability and it is easier to accumulate in vivo.

2. Test compounds in lung homogenate:

Example compounds 7, 12, 61,69, 80, 82, 94, 113, 122 and 131 of the invention

The compounds of the invention were respectively incubated with the Beagle dog lung homogenate for 8 hours in a 37 ° C water bath, and the sample was analyzed by LC-MS / MS when the reaction ended. The area ratio of the 0 min sample was considered as 100%, and the remaining percentage of the compounds after incubation for 8 hours was obtained by comparison with the sample after 8 hours. The results are shown in Table 8.

Table 8 Conditions of metabolic stability of the compounds of the invention in lung homogenate in vitro (8 h)

Conclusion: The above tests show that the compounds of the invention are stable in the lung and thus have a long-acting effect in the lung. As can be seen from Table 7, the compounds of the invention have poor metabolic stability in SD rat and Beagle dog liver microsomes, are more rapidly metabolized and are difficult to accumulate in vivo, while the control compound has better metabolic stability. and it is easier to accumulate. It shows that the compounds of the invention cannot accumulate effective toxic doses.

Preparation example 1

A dry powder preparation for administration by inhalation was prepared by the following method:

Each component and quantity of it in the composition were:

Compound 59 of the invention 0.20 mg

Lactose 30 mg

The compound of the invention was micronized, sufficiently mixed with the micronized lactose, and the mixture was loaded into a gelatin suction cartridge and administered by a powder inhaler.

Preparation example 2

A dry powder preparation for use in a dry powder inhalation device was prepared by the following method:

Compound 70 of the invention was micronized, and mixed with the micronized lactose uniformly to form a preparation. The combination ratio of the preparation was 1: 200, and the preparation composition was loaded into a dry powder inhalation device capable of transferring 10 gg to 100 gg of the compound of the invention.

Preparation example 3

A dry powder preparation was prepared for use in a metered dose inhalation inhalation administration by the following method:

10 g of the micronized compound 99 of the invention having an average particle size of less than 10 gm was dispersed in 200 mL of soft water solution containing 0.2 g of lecithin to form a suspension containing 5% by weight of the compound of the invention and 0.1% by weight of lecithin, and the suspension was spray dried to form particles having an average particle size less than 1.5 gm. The particles were loaded into pressurized 1,1,1,2-tetrafluoroethane cartridges.

Preparation example 4

The pharmaceutical composition for use in a metered dose inhaler was prepared by the following method:

5 g of the micronized compound 138 of the invention having an average particle size less than 10 gm was dispersed in 100 mL of a soft water colloid containing 0.5 g of trehalose and 0.5 g of lecithin to form a suspension. containing 5% by weight of the compound of the invention, 0.5% of trehalose and 0.5% by weight of lecithin. The suspension was spray dried to form particles having an average particle size less than 1.5 gm. The particles were loaded into pressurized 1,1,1,2-tetrafluoroethane cartridges.

Claims (149)

1. A compound represented by formula I, or a pharmaceutically acceptable salt, solvate, optical isomer thereof:

in formula I, having all the carbons marked with * the (R) configuration, where: L is (C4-10) aryl or heteroaryl where the heteroaryl heteroatom is selected from N, O and S, and the above groups may be unsubstituted or optionally substituted with one or more substituents selected from halogen, -OR1, -SR1 , -NR1R2, -NHCOR1, -CONR1R2, -CN, ^{-NO 2} , -COOR1, -CF ³ and linear or branched ^{C 1} -C ^{4 hydrocarbyl;} W is independently selected from substituted or unsubstituted (3-7C) cycloalkyl, the substituent is selected from halogen, (1-4C) alkyl, (1-4C) alkoxy, alkoxyhydrocarbyl, and heterocycle; R ¹ is a divalent group - (R ¹ a) d- (A ¹ ) e- (R ¹ b) f-; where d, e, and f are each independently selected from 0, 1,2, or 3, and the number of contiguous atoms in the shortest chain between two nitrogen atoms to which R ¹ binds is in the range of 3 to 14 ; R ^{1 a} and R ¹ b are each independently selected from (1-10C) alkylene, (2-10C) alkenylene, (1-4C) alkyleneoxy, alkyleneoxyalkyl, alkyleneamido, alkylenazyloxy, and alkyleneamino, wherein each from alkylene, alkenylene, alkyleneoxy, alkyleneoxyalkyl, alkyleneamino, alkylenazyloxy, alkyleneamido is unsubstituted or substituted with substituents independently selected from (1-4C) alkyl, chlorine, fluoro, hydroxy, phenyl and substituted phenyl, R ^{1 a} and R ¹ b may be the same or different; A ¹ is independently selected from (C3-7) cycloalkylene, (C2-7) alkylene, (C6-10) arylene, (C4-9) heteroarylene, and (C3-8) heterocycloalkylene, where cycloalkylene may be unsubstituted or substituted with 1-4 substituents independently selected from (1-6C) alkyl; each of arylene, heteroarylene and heterocycloalkylene may be unsubstituted or substituted with 1-3 substituents independently selected from halogen, (1-6C) alkyl, (1-6C) alkoxy, -S (1-4C) alkyl, -S (O) -C 1-4 alkyl, -S (O) ² -C 1-4 alkyl, -C (O) -O (1-4C) alkyl, -NH (1-4C) alkyl, -N = [(1-4C) alkyl] 2, carboxy, nitro, cyano, amido, ester group, trifluoromethyl and trifluoromethoxy; R ² is selected from -N (R ² a) C (R ² b) (O), -C (R ² c) (R ² d) OR ² e, -N (R ² f) - and -O- ; R ³ is selected from hydrogen, -C (Rsa) = C (R3b) -C (O) -, -OC (R3c) (R3d) C (O) -, -N (R3e) CH (Raf) C (O ) -, -C (R3g) (R3h) S (O) 2- and -SCO-; provided that when R ³ is hydrogen, R ² is selected from -N (R ² a) C (R ² b) (O) and -C (R ² c) (R ² d) OR ² e; when R ³ is selected from -C (R3a) = C (R3b) -C (O) -, -OC (R3c) (R3d) C (O) -, -N (R3e) CH (R3f) C (O) -, -C (R3g) (R3h) S (O) 2- and -SCO-, R ² is selected from -N (R ² f) - and -O-; R ^{2 a- 2} f and R 3a-3h are each independently selected from hydrogen and (1-4C) alkyl; Y- is selected from pharmaceutically acceptable acid radicals, including inorganic and organic acid radicals; Y T represents a hydroxy position on the benzene ring, and is selected from the ortho or meta position of R ² on the benzene ring. 2. The compound according to claim 1, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, wherein L is an unsubstituted phenyl, pyridyl, furyl or thienyl. 3. The compound according to claim 1 or claim 2, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, wherein W is unsubstituted (C3-7) cycloalkyl. 4. The compound according to claim 3, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, wherein W is cyclobutyl, cyclopentyl or cyclohexyl. The compound according to claim 1, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, wherein R ^{1 a} and R ¹ b are each independently selected from (1-10C) alkylene, -C 1-4alkyleneoxy , alkyleneamido; and A ¹ is independently selected arylene (C6-10), where the arylene may be unsubstituted or substituted with 1-2 substituents independently selected from halogeno, (1-6C) alkyl, (1-6C) alkoxy, carboxy, nitro, cyano, amido and ester group. 6. The compound according to claim 1, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, wherein R ¹ is selected from: - (CH2) 3-, - (CH ² H-, - (CH ² ) ⁸ -, - (CH2) 9-, - (CH ² ) ¹⁰ -, - (CH ² ) ² O (CH ² ) ² -, - (CH2) 2O (CH2) 4-, - (CH2) 3O (CH2) 4-, - (CH2) 4O (CH2) 4-, - (CH2) 5O (CH2) 4-, - (CH2) 2O (CH2) 2O (CH2) 2-, - (CH2) 2O (CH2) 3O ( CH2) 2-, -CH2O (CH2) 5OCH2-, - (CH ² ) ² O (CH ² ) ² O (CH ² ) ² O (CH ² ) ² -, - (CH2) 2O (phen-1,4 -ylene) (CH2) 2-, - (CH2) 3O (phen-1,4-ylene) CH2-, - (CH2) 3O (3,5-dichloro-phen-1,4-ylene) CH2-, - (CH2) 2CONH (2-methoxy-5-chloro-phen-1,4-ylene) CH2-, - (CH2) 2CONH (3-methyl-phen-1,4-ylene) CH2-, - (CH ² ) ² CONH ⁽² - methoxy-Fen ^1, 4-ilen) CH2-, - (CH ^{2) 2} CONH (Fen ^1, 4-ilen) CH2-, - (CH2) 3CONH (phen-1,4-ilen ) CH (CH3) -, - (CH2) 3OCH2 (3-methoxy-phen-1,4-ylene) CH (CH3) -, - (CH2) 3O (phen-1,4-ylene) C (CH3) 2 -, - (CH2) 3O (phen-1,4-ylene) CH (CH2CH3) -, - (CH2) 3O (phen-1,4-ylene) (CH2) 2-, - (CH2) 3O (phen- 1,4-ilen) (CH2) 3-, - (CH2) 3O (phen-1,4-ilen) CH2CH (CH3) -, - (CH ^{2) 2} OCH ² (Fen ^1, 4-ilen) CH2O (CH2) 2-, - (CH ² ) ² OCH ² (phen- ¹ , 4 -ilen) CH (CH3) -, - (CH ^{2) 2} O (Fen ^1, 4-ilen) O (CH2) 2-, - (CH2) 3O (2-methoxy-phen-1,4-ilen) O (CH2) 3-, - (CH2) 3O (phen-1,4-ylene) O (CH2) 3-, - (CH2) 3O (phen-1,4-ylene) CH2C (CH3) 2-, - (CH2) 2O (phen-1,4-ylene) CH2C (CH3) 2-, - (CH2) 2O (phen-1,4-ylene) CH2CH (CH3) -, and - (CH2) 2O (phen-1 , 4-ylene) (CH2) 2-, - (CH2) 2O (CH2) 3O (CH2) 2-, 7. The compound according to claim 1, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, wherein R ^{2 a- 2} f are each hydrogen or wherein R3a-3f are each hydrogen. 8. The compound according to claim 1, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, wherein Y- is selected from Br-, Cl-, I-, bicarbonate, carbonate, bisulfate, sulfate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate, phosphite, formate, acetate, propionate, isobutyrate, methanesulfonate, p-toluenesulfonate, benzoate, oxalate, tartrate, fumarate, malonate, succinate, suberate, mandelate, phthalate, benzenesulfonate, citrate, glucuronate radical amino acid. The compound according to claim 1, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, having a structure of the formula la, Ib, Ic or Id:

wherein: the carbons marked with * are the (R) configuration, and L, W, Ri and Y are in accordance with those in claim 1. 10. The compound according to claim 1 or claim 9, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, having a structure of the formula Ia1, Ib1, Ic1 or Id1:

wherein: the carbons marked with * are the (R) configuration, and Ri and Y are in accordance with those in claim 1. The compound according to claim 1, or the pharmaceutically acceptable salt, solvate, optical isomer thereof, which is: (1) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(R) -2- (3-hydroxymethyl) bromide -4-hydroxy) phenyl-2-hydroxyethylamino] propyl} -1-azabicyclo [2,2,2] octylonium; (2) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (3 - {(R) - [2-hydroxy-2 bromide - (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propyl) -1-azabicyclo [2,2,2] octylonium; (3) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {4 - [(R) -2- (3-hydroxymethyl) bromide -4-hydroxy) phenyl-2-hydroxyethylamino] butyl} -1-azabicyclo [2,2,2] octylonium; (4) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (4 - {(R) - [2-hydroxy-2 - (3-formamido-4-hydroxy) phenyl] ethylamino} butyl-1-azabicyclo [2,2,2] octylonium; (5) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9 - {- [(R) - [2-hydroxy bromide -2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} nonyl) -1-azabicyclo [2,2,2] octylonium; (6) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopropyl-2-phenyl] ethoxy-1 - (8 - {(R) - [2- (3- hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} octylph-1-azabicyclo [2,2,2] octylonium; (7) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9 - {(R) - [2- (3- hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino-} nomylf-1-azabicyclo [2,2,2] octylonium; (8) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (10 - {(R) - [2- ( 3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} decyl) -1-azabicyclo [2,2,2] octylonium; (9) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (11 - {(R) - [2- (3- hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} tetradecyl) -1-azabicyclo [2,2,2] octylonium; (10) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (4 - {(R) - [2-hydroxy-2 - (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} butyl) -1-azabicyclo [2,2,2] octylonium; (11) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclobutyl-2-phenyl] ethoxy-1 - (8 - {(R) - [2-hydroxy-2 bromide - (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} octyl) -1-azabicyclo [2,2,2] octylonium; (12) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9 - {(R) - [2-hydroxy-2 bromide - (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} nonyl) -1-azabicyclo [2,2,2] octylonium; (13) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (10 - {(R) - [2-hydroxy-2 - (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} decyl) -1-azabicyclo [2,2,2] octylonium; (14) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (11 - {((R) - [2-hydroxy- 2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} undecyl) -1-azabicyclo [2,2,2] octylonium; (15) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2- (3-methyl) phenyl] ethoxy-1 - (3 - {(R) - [bromide 2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propyl) -1-azabicyclo [2,2,2] octylonium; (16) Bromide of (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (8 - {(R) - [2-hydroxy-2 - (3-formamido-4-hydroxy) phenyl] ethylamino} octyl) -1-azabicyclo [2,2,2] octylonium; (17) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (9 - {(R) - [2-hydroxy-2 bromide - (3-formamido-4-hydroxy) phenyl] ethylamino} nonyl) -1-azabicyclo [2,2,2] octylonium; (18) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (10 - {(R) - [2-hydroxy-2 - (3-formamido-4-hydroxy) phenyl] ethylamino} decyl) -1-azabicyclo [2,2,2] octylonium; (19) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (11 - {(R) - [2-hydroxy-2 bromide - (3-formamido-4-hydroxy) phenyl] ethylamino} undecyl) -1-azabicyclo [2,2,2] octylonium; (20) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (3 - {- [(R) - [2-hydroxy -2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} propyl) -1-azabicyclo [2,2,2] octylonium; (21) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (4 - {- [(R) - [2-hydroxy -2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butyl) -1-azabicyclo [2,2,2] octylonium; (22) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2- (4-isobutyl) phenyl] ethoxy-1 - (8 - {- [(R) bromide) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} octyl) -1-azabicyclo [2,2,2] octylonium; (23) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (10 - {- [(R) - [2-hydroxy -2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} decyl) -1-azabicyclo [2,2,2] octylonium; (24) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (11 - {(R) - [2-hydroxy-2 bromide - (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} undecyl) -1-azabicyclo [2,2,2] octylonium; (25) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} butoxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (26) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4 - {(R) - [2- hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butoxy) pentyl] 1-azabicyclo [2,2,2] octylonium; (27) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [4- (4 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} butoxy) butyl-1-azabicyclo [2,2,2] octylonium; (28) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} butoxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (29) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} butoxy) pentyl] -1-azabicyclo [2,2,2] octylonium; (30) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [3- (4 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} butoxy) propyl] -1-azabicyclo [2,2,2] octylonium; (31) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2- (4-methoxy) phenyl] ethoxy-1 - [2- (2 - {(R) bromide ) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethoxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (32) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4 - {(R) - [2- hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} butoxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (33) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4 - {(R) - [2- hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} heptoxy) hexyl] -1-azabicyclo [2,2,2] octylonium; (34) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [3- (4 - {(R) - [2- hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} butoxy) propyl] -1-azabicyclo [2,2,2] octylonium; (35) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [4- (4 - {(R) - [2- hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} butoxy) butyl] -1-azabicyclo [2,2,2] octylonium; (36) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (2 - {(R) - [2- hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethyloxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (37) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [5- (4 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} butoxy) pentyl] -1-azabicyclo [2,2,2] octylonium; (38) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2- (3-methyl-4-methoxy) phenyl] ethoxy-1- [3- (4) bromide - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} butoxy) propyl] -1-azabicyclo [2,2,2] octylonium; (39) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [4- (4 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} butoxy) butyl] -1-azabicyclo [2,2,2] octylonium; (40) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (2 - {(R) - [2- hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethoxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (41) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [2- (4 - {(R) - [2- hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butoxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (42) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy- [3- (4 - {(R) - [2-hydroxy- 2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butoxy) propyl] -1-azabicyclo [2,2,2] octylonium; (43) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy- [4- (4 - {(R) - [2-hydroxy- 2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} butoxy) butyl] -1-azabicyclo [2,2,2] octylonium; (44) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy- [2- (2 - {(R) - [2-hydroxy- 2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxy) ethyl] -1-azabicyclo [2,2,2] octylonium; (45) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- {2- [2- (2 - {( R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethoxy) ethoxy] ethoxy} ethyl) -1-azabicyclo [2,2,2] octylonium; (46) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [2- (2 - {(R) - chloride) [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethoxy) ethoxy] ethyl} (1) -azabicyclo [2,2,2] octylonium; (47) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- [2- (2 - {(R) - chloride) [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethoxy) ethoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (48) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- [3- (2 - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethoxy) propoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (49) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- {2- [2- (2 - {( R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethoxy) propoxy] propoxy} propyl) -1-azabicyclo [2,2,2 ] octylonium; (50) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- [2- (2 - {(R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethoxy) ethoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (51) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- [3- (2 - {(R) - bromide) [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethoxy) propoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (52) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- {2- [2- (2 - {( R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethoxy) ethoxy] ethoxy} ethyl) -1-azabicyclo [2,2,2] octylonium; (53) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- [3- (2 - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propoxy) pentoxy] butyl} -1-azabicyclo [2,2,2] octylonium; (54) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- {2- [2- (2 - {( R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxy) ethoxy] ethoxy} ethyl) -1-azabicyclo [ 2,2,2] octylonium; (55) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [2- (2 - {(R) - chloride) [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxy) ethoxy] ethyl} -1-azabicyclo [2,2,2 ] octylonium; (56) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - (2- [3- (2 - {(R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxy) propoxy] ethyl} -1-azabicyclo [2,2,2 ] octylonium; (57) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2 - {(R) bromide) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] ethyl]} -1-azabicyclo [2,2,2] octylonium; (58) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl)] ethoxy-1 - {2- [4- (2 - {(R) benzoate) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] ethyl]} -1-azabicyclo [2,2,2] octylonium; (59) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (60) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(3,5-dichloro-4- ( 1 - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) phenoxy) propyl} -1-azabicyclo [2,2,2] octylonium; (61) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide) [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} isobutyl) phenoxy] ethyl} -1-azabicyclo [2,2,2 ] octylonium; (62) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy] -1 - {2- [4- (2 - {(R) bromide) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (63) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (64) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3 - [(4- (3-methyl-1 - {(R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethylidene) phenoxy] propyl} -1-azabicyclo [ 2,2,2] octylonium; (65) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (66) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-thienyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (67) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} propyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (68) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} propyl) phenoxy] heptanyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (69) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3,5-dichloro-1) bromide - {(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (70) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4 - ({(R) - [2) bromide - (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxyethylamino] ethylidene} phenoxy) propyl] -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (71) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [3- (3-methoxy-4 - {[(R) bromide ) -2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxyethylamino] ethylidene} phenoxy) propyl] -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (72) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} isopropylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (73) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide 2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} propylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (74) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} isobutyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (75) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} isobutyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (76) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} propyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (77) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methyl-4- (1 - { (R) - [2- (3-Hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethylidene) phenoxy] propyl-1-azabicyclo [2,2,2] octylonium (racemic, S-isomer, R-isomer) ; (78) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - acetate) (2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (79) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2- (4-chloro) phenyl] ethoxy-1 - {3- [4- (2- {(R) - (2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethyl) phenoxy] propyl} -1-azabicyclo [2,2,2 ] octylonium; (80) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - bromide) (2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (81) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propyl) phenoxy] propyl} -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (82) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-furyl] ethoxy-1 - {3- [3,5-dichloro- (4- { (R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (83) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethylidene) phenoxy] propyl} -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (84) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methoxy-4 - {((R) bromide ) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino] ethylidene} phenoxy) propyl] -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (85) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} isopropylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (86) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - [3- (4- {2 - [(R) - 2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino] isobutyl} phenoxy) propyl] -1-azabicyclo [2,2,2] octylonium; (87) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide) [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} isobutyl) phenoxy] ethyl} -1 -azabicyclo [2,2,2] octylonium; (88) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide) [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propyl) phenoxy] ethyl} -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (89) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methyl-4- (1 - { (R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octilonium (racemic, S isomer, R isomer); (90) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (91) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (92) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (93) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - bromide) [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (94) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide) [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (95) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (96) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methoxy-4- (1 - { (R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethylidene) phenoxy] propyl} -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer ); (97) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide) [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} isopropylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (98) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (99) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} isobutyl) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (100) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclohexyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} isobutyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (101) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methyl-4- (1 - { (R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethylidene) phenoxy] propyl} -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer ); (102) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide) [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethyl) phenoxy] ethyl} -1-azabicyclo [2,2,2 ] octylonium; (103) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide) [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [2,2,2 ] octylonium; (104) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethyl) phenoxy] propyl} 1-azabicyclo [2,2,2] octylonium; (105) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - bromide) [2-hydroxy-2- (5-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} propyl) phenoxy] propyl} -1-azabicyclo [2,2,2 ] octylonium; (106) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide 2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} propyl) phenoxy] propyl} -1 -azabicyclo [2,2,2] octilonium (racemic, S isomer, R isomer); (107) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-pyridyl] ethoxy-1 - {3- [3,5-dichloro-4- (1) bromide - [(R) -2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} methyl) phenoxy] propyl} -1-azabicyclo [ 2,2,2] octylonium; (108) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethylidene) phenoxy] propyl} -1 -azabicyclo [2,2,2 ] octylonium (racemic, S isomer, R isomer); (109) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methoxy-4- (1 - { (R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethylidene) phenoxy] propyl-1 -azabicyclo [2, 2,2] octylonium (racemic, S isomer, R isomer); (110) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide) [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl) ethylamino} isopropylidene) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (111) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (1 - {(R) - bromide 2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} propylidene) phenoxy] propyl} -1 -azabicyclo [2,2,2] octilonium (racemic, S isomer, R isomer); (112) (R) - (-) - 3 - [(R) -2-hydroxy-2-suberyl-2-phenyl] ethoxy-1 - {3- [4- (2 - {(R) - bromide) [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} isobutyl) phenoxy] propyl-1-azabicyclo [2,2,2] octylonium; (113) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} propyl) phenoxy] ethyl-1-azabicyclo [2,2,2] octilonium (racemic, S isomer, R isomer); (114) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {3- [4- (3 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (115) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethyoxyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (116) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {3- [5-chloro-2-methoxy-4- bromide ({(R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2, 2] octylonium; (117) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4 - ({(R) - [2) bromide -hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium ; (118) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethylidene) benzyloxy] ethyl} -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (119) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide) 2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxymethyl) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (120) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-naphthyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethoxymethyl) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (121) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (1 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} ethylidene) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (122) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [2-methoxy-4- (3- { (R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (123) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - bromide [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (124) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [5-chloro-2-methoxy-4- bromide ({(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium; (125) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2- (4-hydroxy) phenyl] ethoxy-1 - {3- [2-methoxy-4 bromide - ({(R) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium; (126) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methyl-4 - ({(R ) - [2- (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium; (127) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4 - ({(R) [- 2 - (3-hydroxymethyl-4-hydroxy) phenyl-2-hydroxy] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium; (128) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethoxymethyl) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (129) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (1 - {(R) - bromide [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} ethylidene) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (130) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide) [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) yl] ethylamino} ethoxy) phenoxy] ethyl} -1 -azabicyclo [2,2,2] octylonium; (131) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [2-methoxy-4- (3- { (R) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (132) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - bromide) [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (133) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [2-methoxy-4 - ({(R ) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octilonium; (134) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methyl-4 - ({(R ) - [2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octilonium; (135) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4 - ({(R) - [2 -hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium; (136) (R) - (-) - 3 - [(R) -2-hydroxy-2- (3-ethyl) cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2- {(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethoxymethyl) benzyloxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (137) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} ethyoxyl) phenoxy] ethyl} -1-azabicyclo [2,2,2] octylonium; (138) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [2-methoxy-4- (3- { (R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2] octylonium; (139) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [5-chloro-2-methoxy-4- bromide ({(R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium; (140) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [2-methoxy-4 - ({(R) ) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) anilino] oxopropyl-1-azabicyclo [2,2,2] octylonium; (141) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1- {3- [3-methyl-4 - ({(R ) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2,2] octylonium; (142) (R) - (-) - 3 - [(R) -2-hydroxy-2- (3-methoxy) cyclopentyl-2-phenyl] ethoxy-1 - {3- [4 - ({( R) - [2-hydroxy-2- (3-formamido-4-hydroxy) phenyl] ethylamino} methyl) anilino] oxopropyl-1-azabicyclo [2,2,2] octylonium; (143) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethylidene) benzyloxyethyl} -1 -azabicyclo [2,2,2] octylonium (racemic, S isomer, R isomer); (144) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {2- [4- (2 - {(R) - bromide [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} ethoxy) phenoxy] ethyl} -1-azabicyclo [2,2,2 ] octylonium; (145) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [2-methoxy-4- (3- { (R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2 , 2.2] octylonium; (146) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [4- (3 - {(R) - bromide [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} propoxy) phenoxy] propyl} -1-azabicyclo [2,2,2 ] octylonium; (147) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [5-chloro-2-methoxy-4- bromide ({(R) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl) ethyl] amino} methyl) anilino] oxopropyl} -1- azabicyclo [2,2,2] octylonium; (148) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [2-methoxy-4 - ({(R ) - [2-hydroxy-2- (6-hydroxy-2H-1 ^ -benzoxazin ^^ H ^ one ^ -il ^ ethylam ino ^ etiO anilino ^ xopropylH -azabicyclo ^^^ octilon io; or (149) (R) - (-) - 3 - [(R) -2-hydroxy-2-cyclopentyl-2-phenyl] ethoxy-1 - {3- [3-methyl-4 - ({(R ) - [2-hydroxy-2- (6-hydroxy-2H-1,4-benzoxazin-3 (4H) -ona-8-yl)] ethylamino} methyl) anilino] oxopropyl} -1-azabicyclo [2,2 , 2] octylonium. 12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, optical isomer thereof, for use in treating the human or animal body by therapy. 13. A pharmaceutical composition comprising a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, optical isomer and a pharmaceutically acceptable carrier thereof, wherein the composition may be in any suitable dosage form, preferably dosage forms for administration by inhalation or administration by nasal administration; and the additional composition may or may not contain one or more other drugs that can be used for administration by combination. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition comprises a therapeutically effective amount of a steroidal anti-inflammatory drug or a therapeutically effective amount of a PDE4 inhibitor. The pharmaceutical composition according to claim 13, wherein the one or more other drugs is a bronchodilator, an anti-inflammatory agent, an M receptor agonist; an anti-infective agent, an antihistamine, a protease inhibitor or an afferent blocker, and optionally wherein: (a) the bronchodilator is a PDE ³ inhibitor or a P ² adrenoreceptor agonist; (b) the anti-inflammatory agent is a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, or a PDE ⁴ inhibitor; (c) the anti-infective agent is a Gram-negative antibiotic, a Gram-positive antibiotic, or an antiviral drug; or (d) the afferent blocker is a D ² agonist. 16. A method of preparing a compound of formula I, or a pharmaceutically acceptable salt, solvate, optical isomer thereof, comprising the steps of: (a) reacting intermediate 1 or salt thereof with X ¹ -R ¹ -X ² to produce intermediate 2; (b) reacting intermediate 2 with intermediate 3 to produce intermediate 4 with protecting groups; (c) deprotecting the groups of intermediate 4 or another compound of formula I with protecting groups to obtain the compound of formula I; Y (d) exchanging the compound of formula I with a basic anion exchange resin to generate a hydroxide of formula I, and then reacting with various acids to prepare quaternary ammonium salts with various acid radicals; or exchanging the compound of formula I with a specific anion exchange resin to prepare a quaternary ammonium salt with a specific acid radical; or reacting a halide of the formula I with silver oxide to generate a hydroxide of the formula I and then reacting with other acids to generate quaternary ammonium salts with various acid radicals; or reacting a halide of formula I with a silver salt to produce a quaternary ammonium salt with a corresponding acid radical;

where the carbons marked with * in intermediates 1,2, 3, 4 designate the R configuration; Xi and X ² in compound X ¹ -R ¹ -X ² are leaving groups or amino groups, and the leaving groups are selected from halogen such as chlorine, bromine and iodine, and sulfonates such as methanesulfonate, p-toluenesulfonate and carbonyl; Z is a leaving group or -NHQ ² , and the leaving group is selected from halogen such as chlorine, bromine, and iodine, and sulfonates such as methanesulfonate, p-toluenesulfonate, and carbonyl, provided that when X ² is a leaving group , Z is -NHQ ² , and when X ² is selected from amino group, Z is the leaving group; Q ¹ is hydrogen or a hydroxy protecting group selected from silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl, esters (acyl groups) such as formyl and acetyl, and arylmethyl groups such as benzyl, p-methoxybenzyl, 9- fluorenylmethyl and benzhydryl; Q ² is hydrogen or an amino protecting group selected from benzyl (Bn), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, and acetyl; R is (1-6C) alkyl, phenyl or substituted phenyl, preferably methyl, ethyl, p-tolyl or phenyl; R ¹ , R ² , R ³ , Y are the same as defined in claim 1; Y In the method, when one of the starting materials is salt, the salt is normally neutralized before or during the reaction, and said neutralization is normally carried out with a base whose molar equivalent is equal to that of the salt. 17. A compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, optical isomer thereof, or the pharmaceutical composition of any one of claims 13 to 15, for use in the preparation of a medicament as a bronchodilator or to treat respiratory disease, optionally wherein the respiratory disease includes a pulmonary disorder, a disease related to reversible airway obstruction, COPD, asthma, rhinitis or pulmonary fibrosis.